Substituted pyridazines and 1,2,4-triazines as prostacyclin receptor modulators

ABSTRACT

Cyclohexane derivatives of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the PGI2 receptor. 
                         
Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pulmonary arterial hypertension (PAH) and related disorders; platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina; stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; blood clot formation in an angioplasty or coronary bypass surgery individual or in an individual suffering from atrial fibrillation; atherosclerosis; atherothrombosis; asthma or a symptom thereof; a diabetic-related disorder such as diabetic peripheral neuropathy, diabetic nephropathy or diabetic retinopathy; glaucoma or other disease of the eye with abnormal intraocular pressure; hypertension; inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis; Crohn&#39;s disease; transplant rejection; multiple sclerosis; systemic lupus erythematosus (SLE); ulcerative colitis; ischemia-reperfusion injury; restenosis; atherosclerosis; acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructive pulmonary disorder (COPD).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/230,825, filed Aug. 8, 2016, now U.S. Pat. No. 10,138,210, issuedNov. 27, 2018, which is a divisional of U.S. application Ser. No.14/566,019, filed Dec. 10, 2014, now abandoned, which is a divisional ofU.S. application Ser. No. 13/133,036, filed Jun. 6, 2011, now U.S. Pat.No. 8,940,891, issued Jan. 27, 2015, which is a U.S. National Stageentry of International Application No. PCT/US2009/006408, filed Dec. 7,2009, which claims the benefit of priority from U.S. ProvisionalApplication No. 61/205,726, filed Jan. 22, 2009, and U.S. ProvisionalApplication No. 61/201,150, filed Dec. 8, 2008, all of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to certain compounds of Formula Ia andpharmaceutical compositions thereof that modulate the activity of thePGI2 receptor. Compounds of the present invention and pharmaceuticalcompositions thereof are directed to methods useful in the treatment of:pulmonary arterial hypertension (PAH); idiopathic PAH; familial PAH; PAHassociated with: a collagen vascular disease, a congenital heartdisease, portal hypertension, HIV infection, ingestion of a drug ortoxin, hereditary hemorrhagic telangiectasia, splenectomy, pulmonaryveno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis(PCH); PAH with significant venous or capillary involvement; plateletaggregation; coronary artery disease; myocardial infarction; transientischemic attack; angina; stroke; ischemia-reperfusion injury;restenosis; atrial fibrillation; blood clot formation in an angioplastyor coronary bypass surgery individual or in an individual suffering fromatrial fibrillation; atherothrombosis; asthma or a symptom thereof; adiabetic-related disorder such as diabetic peripheral neuropathy,diabetic nephropathy or diabetic retinopathy; glaucoma or other diseaseof the eye with abnormal intraocular pressure; hypertension;inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis;Crohn's disease; transplant rejection; multiple sclerosis; systemiclupus erythematosus (SLE); ulcerative colitis; atherosclerosis; acne;type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructivepulmonary disorder (COPD).

BACKGROUND OF THE INVENTION

Prostacyclin (PGI2) is a lipid molecule derived from arachidonic acidthrough the cyclooxygenase pathway. It is a potent vasodilator,antiproliferative, anti-thrombotic and antiplatelet agent that mediatesits effects as an agonist of a G protein-coupled receptor (PGI2receptor; e.g., human PGI2 receptor, GenBank® Accession No. NP_000951and alleles thereof). It is known that the binding of PGI2 (or othersuch agonist) to the PGI2 receptor leads to coupling with the Gs proteinand increases intracellular cAMP levels. (See, e.g., Zhang et al., Arch.Biochem. Biophys., 2006, 454:80-88.)

Pulmonary arterial hypertension (PAH) is a life-threatening diseasecharacterized by a progressive pulmonary vasculopathy leading to rightventricular hypertrophy. Right heart failure occurs if left untreated.Prostacyclin, which has vasodilatory and antiproliferative effects onthe pulmonary vasculature has been found to be low in patients with PAHcompared with normal controls. Exogenous administration of prostacyclinor an analog of prostacyclin (i.e., an agonist of the PGI2 receptor) hasbecome an important strategy in the treatment of PAH. (See, e.g., Tuderet al., Am. J. Respir. Crit. Care. Med., 1999, 159:1925-1932; Humbert etal., J. Am. Coll. Cardiol., 2004, 43:13S-24S; Rosenzweig, Expert Opin.Emerging Drugs, 2006, 11:609-619; McLaughlin et al., Circulation, 2006,114:1417-1431; Rosenkranz, Clin. Res. Cardiol., 2007, 96:527-541;Driscoll et al., Expert Opin. Pharmacother., 2008, 9:65-81.)

Trepostinil and iloprost are FDA-approved analogs of prostacyclin which,like prostacyclin, are not orally-active. Beraprost is an orally-activeanalog of prostacyclin approved for the treatment of PAH in Japan, butit has failed registration for the treatment of PAH in Europe and in theUS. Of the three FDA-approved drugs, prostacyclin is the best studied inPAH patients. The approximate annual cost of treating PAH with thesedrugs is $25,000 to $200,000 depending on the dose. At present, manyexperts consider intravenous prostacyclin to be the most reliable agentfor managing the sickest PAH patients. Due to the short half-life ofprostacyclin, intravenous treatment is complicated by the need for acontinuous infusion. Patients are at risk for potentially fatal reboundpulmonary hypertension if the infusion is abruptly disrupted, as well assignificant risk of catheter-related complications including sepsis.(See, e.g., Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619;Naeije et al., Expert Opin. Pharmacother., 2007, 8:2247-2265; Strauss etal., Clin. Chest. Med., 2007, 28:127-142; Driscoll et al., Expert Opin.Pharmacother., 2008, 9:65-81.)

There is considerable interest in developing prostacyclin analogs (i.e.,agonists of the PGI2 receptor) for use in the treatment of otherdiseases, such as atherothrombosis. Developing stable, orally-activeanalogs of prostacyclin (i.e., stable, orally-active agonists of thePGI2 receptor) is a rate-limiting step in achieving this goal (see,e.g., Arehart et al., Curr. Med. Chem., 2007, 14:2161-2169; Arehart etal., Circ. Res., 2008, 102(8), 986-93), as well as in the improvedmanagement of PAH.

SUMMARY OF THE INVENTION

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ia and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: H and C₁-C₈ alkyl;

R² and R³ are each independently selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₅haloalkyl and halogen; and

X is selected from: N and CH.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a compound of the present invention and apharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for thetreatment of a PGI2 receptor mediated disorder in an individual,comprising administering to the individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH in an individual, comprising administering to theindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of idiopathic PAH in an individual, comprising administeringto the individual in need thereof, a therapeutically effective amount ofa compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of familial PAH in an individual, comprising administering tothe individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease in anindividual, comprising administering to the individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease selectedfrom: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis in an individual, comprising administering to theindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease in anindividual, comprising administering to the individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease selectedfrom: atrial septic defect (ASD), ventricular septic defect (VSD) andpatent ductus arteriosus in an individual, comprising administering tothe individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with portal hypertension in an individual,comprising administering to the individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with HIV infection in an individual,comprising administering to the individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with ingestion of a drug or toxin in anindividual, comprising administering to the individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with hereditary hemorrhagic telangiectasiain an individual, comprising administering to the individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with splenectomy in an individual,comprising administering to the individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with significant venous or capillaryinvolvement in an individual, comprising administering to the individualin need thereof, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary veno-occlusive disease (PVOD)in an individual, comprising administering to the individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary capillary hemangiomatosis(PCH) in an individual, comprising administering to the individual inneed thereof, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of platelet aggregation in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of: coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, ischemia-reperfusion injury, restenosisor atrial fibrillation in an individual, comprising administering to theindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to the individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of blood clot formation in an individual suffering from atrialfibrillation comprising administering to the individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of atherosclerosis in an individual, comprising administeringto the individual in need thereof, a therapeutically effective amount ofa compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of atherothrombosis in an individual, comprising administeringto the individual in need thereof, a therapeutically effective amount ofa compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of asthma in an individual, comprising administering to theindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of a symptom of asthma in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a diabetic-related disorder in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic peripheral neuropathy in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic nephropathy in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic retinopathy in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of glaucoma or other disease of the eye with abnormalintraocular pressure in an individual, comprising administering to theindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof. In some embodiments the abnormal intraocular pressure isincreased intraocular pressure.

One aspect of the present invention pertains to methods for thetreatment of hypertension in an individual, comprising administering tothe individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of hypertension intended to confer protection against cerebralischemia in an individual, comprising administering to the individual inneed thereof, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of inflammation in an individual, comprising administering tothe individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease in an individual, comprisingadministering to the individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease selected from: psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma in an individual, comprising administering tothe individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods of modulatingthe activity of a PGI2 receptor by contacting the receptor with acompound of the present invention.

One aspect of the present invention pertains to methods of agonizing aPGI2 receptor by contacting the receptor with a compound of the presentinvention.

One aspect of the present invention pertains to methods for thetreatment of PAH selected from: idiopathic PAH; familial PAH; PAHassociated with a collagen vascular disease selected from: scleroderma,CREST syndrome, systemic lupus erythematosus (SLE), rheumatoidarthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAHassociated with a congenital heart disease selected from: atrial septicdefect (ASD), ventricular septic defect (VSD) and patent ductusarteriosus in an individual; PAH associated with portal hypertension;PAH associated with HIV infection; PAH associated with ingestion of adrug or toxin; PAH associated with hereditary hemorrhagictelangiectasia; PAH associated with splenectomy; PAH associated withsignificant venous or capillary involvement; PAH associated withpulmonary veno-occlusive disease (PVOD); and PAH associated withpulmonary capillary hemangiomatosis (PCH) in an individual comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: platelet aggregation, coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis, atrialfibrillation, blood clot formation, atherosclerosis, atherothrombosis,asthma, a symptom of asthma, a diabetic-related disorder, diabeticperipheral neuropathy, diabetic nephropathy, diabetic retinopathy,glaucoma or other disease of the eye with abnormal intraocular pressure,hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoidarthritis, Crohn's disease, transplant rejection, multiple sclerosis,systemic lupus erythematosus (SLE), ulcerative colitis,ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonarydisorder (COPD) in an individual comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a PGI2 receptor mediated disorder.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of idiopathic PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of familial PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with collagen vascular disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a collagen vascular disease selectedfrom: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a congenital heart disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a congenital heart disease selectedfrom: atrial septic defect (ASD), ventricular septic defect (VSD) andpatent ductus arteriosus.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with portal hypertension.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with HIV infection.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with ingestion of a drug or toxin.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with hereditary hemorrhagic telangiectasia.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with splenectomy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with significant venous or capillaryinvolvement.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with pulmonary veno-occlusive disease(PVOD).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with pulmonary capillary hemangiomatosis(PCH).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of platelet aggregation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a PGI2 receptor mediated disorder selected from: coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis and atrialfibrillation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of blood clot formation in an angioplasty or coronary bypasssurgery individual.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of blood clot formation in an individual suffering from atrialfibrillation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of atherosclerosis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of atherothrombosis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a symptom of asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a diabetic-related disorder.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic peripheral neuropathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic nephropathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic retinopathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of glaucoma or other disease of the eye with abnormalintraocular pressure. In some embodiments the abnormal intraocularpressure is increased intraocular pressure.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of hypertension.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of hypertension intended to confer protection against cerebralischemia.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of inflammation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of an inflammatory disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of an inflammatory disease selected from: psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for modulatingthe activity of a PGI2 receptor.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for agonizing aPGI2 receptor.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH selected from: idiopathic PAH; familial PAH; PAHassociated with a collagen vascular disease selected from: scleroderma,CREST syndrome, systemic lupus erythematosus (SLE), rheumatoidarthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAHassociated with a congenital heart disease selected from: atrial septicdefect (ASD), ventricular septic defect (VSD) and patent ductusarteriosus in an individual; PAH associated with portal hypertension;PAH associated with HIV infection; PAH associated with ingestion of adrug or toxin; PAH associated with hereditary hemorrhagictelangiectasia; PAH associated with splenectomy; PAH associated withsignificant venous or capillary involvement; PAH associated withpulmonary veno-occlusive disease (PVOD); and PAH associated withpulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a disorder selected from: platelet aggregation, coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis, atrialfibrillation, blood clot formation, atherosclerosis, atherothrombosis,asthma, a symptom of asthma, a diabetic-related disorder, diabeticperipheral neuropathy, diabetic nephropathy, diabetic retinopathy,glaucoma or other disease of the eye with abnormal intraocular pressure,hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoidarthritis, Crohn's disease, transplant rejection, multiple sclerosis,systemic lupus erythematosus (SLE), ulcerative colitis,ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonarydisorder (COPD).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of the human or animal bodyby therapy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a PGI2 receptor mediateddisorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of idiopathic PAH.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of familial PAH One aspect ofthe present invention pertains to compounds of the present invention foruse in a method of treatment of PAH associated with a collagen vasculardisease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acollagen vascular disease selected from: scleroderma, CREST syndrome,systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu'sarteritis, polymyositis, and dermatomyositis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acongenital heart disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acongenital heart disease selected from: atrial septic defect (ASD),ventricular septic defect (VSD) and patent ductus arteriosus.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with portalhypertension.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with HIVinfection.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withingestion of a drug or toxin.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withhereditary hemorrhagic telangiectasia.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withsplenectomy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withsignificant venous or capillary involvement.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withpulmonary veno-occlusive disease (PVOD).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withpulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of platelet aggregation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of: coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis or atrial fibrillation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of blood clot formation in anangioplasty or coronary bypass surgery individual.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of blood clot formation in anindividual suffering from atrial fibrillation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of atherosclerosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of atherothrombosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of asthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a symptom of asthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a diabetic-relateddisorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic peripheralneuropathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic nephropathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic retinopathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of glaucoma or other diseaseof the eye with abnormal intraocular pressure. In some embodiments theabnormal intraocular pressure is increased intraocular pressure.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of hypertension.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of hypertension intended toconfer protection against cerebral ischemia.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of inflammation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of an inflammatory disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of an inflammatory diseaseselected from: psoriasis, psoriatic arthritis, rheumatoid arthritis,Crohn's disease, transplant rejection, multiple sclerosis, systemiclupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusioninjury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) andasthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of modulating the activity of a PGI2receptor.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of agonizing a PGI2 receptor.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH selected from:idiopathic PAH; familial PAH; PAH associated with a collagen vasculardisease selected from: scleroderma, CREST syndrome, systemic lupuserythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,polymyositis, and dermatomyositis; PAH associated with a congenitalheart disease selected from: atrial septic defect (ASD), ventricularseptic defect (VSD) and patent ductus arteriosus in an individual; PAHassociated with portal hypertension; PAH associated with HIV infection;PAH associated with ingestion of a drug or toxin; PAH associated withhereditary hemorrhagic telangiectasia; PAH associated with splenectomy;PAH associated with significant venous or capillary involvement; PAHassociated with pulmonary veno-occlusive disease (PVOD); and PAHassociated with pulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a disorder selected from:platelet aggregation, coronary artery disease, myocardial infarction,transient ischemic attack, angina, stroke, ischemia-reperfusion injury,restenosis, atrial fibrillation, blood clot formation, atherosclerosis,atherothrombosis, asthma, a symptom of asthma, a diabetic-relateddisorder, diabetic peripheral neuropathy, diabetic nephropathy, diabeticretinopathy, glaucoma or other disease of the eye with abnormalintraocular pressure, hypertension, inflammation, psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis and chronic obstructivepulmonary disorder (COPD).

One aspect of the present invention pertains to compounds for preparinga composition comprising admixing a compound of the present inventionand a pharmaceutically acceptable carrier.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of an experiment which measured the ability ofCompound 68 to inhibit the right ventricle hypertrophic response toMCT-induced pulmonary arterial hypertension in rat at 30 mg/kg.

FIG. 2 depicts a general method for preparing intermediates useful inthe synthesis of compounds of the present invention.Cyclohexane-1,4-dicarboxylic acid is first converted to the diol eitherdirectly or via an ester. The diol is then converted to a sulfonateester intermediate by either by alkylation with tert-butyl bromoacetatefollowed activation with a sulfonyl chloride or alternatively bytreatment first with a sulfonyl chloride followed by alkylation withtert-butyl 2-diazoacetate in the presence of diacetoxyrhodium.

FIG. 3 depicts a general method for preparing 1,2,4-triazin-3(2H)-onesof the present invention. In the first step, an acetic acid derivativeis reacted with an acid chloride in the presence of base to give aβ-ketoester derivative. This undergoes acid mediatedhydrolysis/decarboxylation to give an ethanone derivative. Reaction withtert-butyl nitrite in the presence of base gives an oxime which isreacted with hydrazinecarbothioamide followed by iodomethane to give a3-(methylthio)-1,2,4-triazine intermediate. This is converted to thetriazinone by treatment with MCPBA and then base. The triazinone iscoupled to the sulfonate ester intermediate described in FIG. 2 to givean ester of Formula Ia which is hydrolyzed with acid to give acarboxylic acid of Formula Ia.

FIG. 4 depicts another general method for preparing compounds of thepresent invention. In this method, a 5-halo-1,2,4-triazin-3(2H)-ones ora 5-halopyridazin-3(2H)-one intermediate is reacted with the sulfonateester described in FIG. 2 in the presence of potassium tert-butoxide and18-crown-6 in DMF. The product undergoes a palladium catalyzed couplingto an aryl or heteroaryl boronic acid derivative to give an ester ofFormula Ia which is hydrolyzed with acid to give a carboxylic acid ofFormula Ia.

FIG. 5 depicts another general method for preparing compounds of thepresent invention. Certain pyridazinone intermediates are prepared byreaction of 3,4-dibromo-5-hydroxyfuran-2(5H)-one with an aryl orheteroaryl derivative in the presence of a Lewis acid followed bytreatment with hydrazine. The resulting pyridazinone is reacted with aboronic acid derivative in the presence of a palladium catalyst. Theproduct of that reaction is coupled to the sulfonate ester intermediatedescribed in FIG. 2 to give an ester of Formula Ia. This is hydrolyzedwith acid to give a carboxylic acid of Formula Ia. Alternatively, theorder in which the pyridazinone is coupled to the boronic acid and thesulfonate ester may be reversed.

FIG. 6 depicts another general method for preparing compounds of thepresent invention. Certain furan-2,5-dione derivatives may be convertedto hydroxypyridazinone intermediates by reaction with benzylhydrazine inacetic acid. Subsequent conversion to the chloride and removal of thebenzyl group is achieved by treatment with phosphorous oxychloridefollowed by aluminum chloride. The resulting chloropyridazinoneintermediate is coupled to the sulfonate ester intermediate described inFIG. 2 and treated with a boronic acid in the presence of a palladiumcatalyst to give an ester of Formula Ia. This is hydrolyzed with acid togive a carboxylic acid of Formula Ia.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonists” is intended to mean moieties that interact andactivate the receptor, such as, the PGI2 receptor and initiate aphysiological or pharmacological response characteristic of thatreceptor. For example, when moieties activate the intracellular responseupon binding to the receptor, or enhance GTP binding to membranes.

The term “contact or contacting” is intended to mean bringing theindicated moieties together, whether in an in vitro system or an in vivosystem. Thus, “contacting” a PGI2 receptor with a compound of theinvention includes the administration of a compound of the presentinvention to an individual, preferably a human, having a PGI2 receptor,as well as, for example, introducing a compound of the invention into asample containing a cellular or more purified preparation containing aPGI2 receptor.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The terms “including” and “such as” are illustrative and not limitative.

The term “in need of treatment” and the term “in need thereof,” whenreferring to treatment are used interchangeably to mean a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” is intended to mean any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates and most preferably humans.

The term “modulate or modulating” is intended to mean an increase ordecrease in the amount, quality, response or effect of a particularactivity, function or molecule.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited to,salts, solvates and hydrates of compounds of the present invention;whereby the composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The term “therapeutically effective amount” is intended to mean theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician or caregiver; or in an individual, whichincludes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Chemical Group, Moiety or Radical

The term “C₁-C₆ alkoxy” is intended to mean a C₁-C₆ alkyl radical, asdefined herein, attached directly to an oxygen atom. Some embodimentsare 1 to 5 carbons; some embodiments are 1 to 4 carbons; someembodiments are 1 to 3 carbons; and some embodiments are 1 or 2 carbons.Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,t-butoxy, isobutoxy, sec-butoxy and the like.

The term “C₁-C₆ alkyl” is intended to mean a straight or branched carbonradical containing 1 to 6 carbons. Some embodiments are 1 to 5 carbons.Some embodiments are 1 to 4 carbons. Some embodiments are 1 to 3carbons. Some embodiments are 1 or 2 carbons. Some embodiments are 1carbon. Examples of an alkyl include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,pentyl, isopentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “C₁-C₆ alkylthio” is intended to mean a C₁-C₆ alkyl radicalattached to a sulfur atom (i.e., —S—) wherein the alkyl radical has thesame definition as described herein. Examples include, but are notlimited to, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl,n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl,sec-butylsulfanyl, iso-butylsulfanyl, t-butylsulfanyl, and the like.

The term “aryl” is intended to mean an aromatic ring radical containing6 to 10 ring carbons. Examples include phenyl and naphthyl. In someembodiments aryl is intended to mean phenyl.

The term “18-crown-6” is intended to mean1,4,7,10,13,16-hexaoxacyclooctadecane. The term “C₁-C₆ haloalkyl” isintended to mean a C₁-C₆ alkyl group, defined herein, wherein the alkylis substituted with one halogen up to fully substituted and a fullysubstituted C₁-C₆ haloalkyl can be represented by the formulaC_(n)L_(2n+1) wherein L is a halogen and “n” is 1, 2, 3, 4, 5 or 6. Whenmore than one halogen is present then they may be the same or differentand selected from the group consisting of F, Cl, Br and I, preferably F.Some embodiments are 1 to 5 carbons, some embodiments are 1 to 4carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1or 2 carbons. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “halogen” or “halo” is intended to mean to a fluoro, chloro,bromo or iodo group.

The term “heteroaryl” is intended to mean an aromatic ring systemcontaining 5 to 14 aromatic ring atoms that may be a single ring, twofused rings or three fused rings wherein at least one aromatic ring atomis a heteroatom selected from, but not limited to, the group consistingof O, S and N wherein the N can be optionally substituted with H, C₁-C₄acyl or C₁-C₄ alkyl. Some embodiments contain 5 to 6 ring atoms forexample furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyland the like. Some embodiments contain 8 to 14 ring atoms for examplecarbazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl,isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl,benzothienyl, benzofuranyl, isobenzofuran and the like.

Compounds of the Invention

One aspect of the present invention pertains to certain compounds asshown in Formula Ia:

and pharmaceutically acceptable salts, solvates and hydrates thereofwherein R¹, R², R³ and X have the same definitions as described herein,supra and infra.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R¹, R², R³ and X) contained within the generic chemical formulaedescribed herein, for example, Ia, Ic, Ie, Ig, Ii, etc., arespecifically embraced by the present invention just as if each and everycombination was individually explicitly recited, to the extent that suchcombinations embrace compounds that result in stable compounds (i.e.,compounds that can be isolated, characterized and tested for biologicalactivity). In addition, all subcombinations of the chemical groupslisted in the embodiments describing such variables, as well as allsubcombinations of uses and medical indications described herein, arealso specifically embraced by the present invention just as if each andevery subcombination of chemical groups and subcombination of uses andmedical indications was individually and explicitly recited herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers and the like. Tautomeric forms can be in equilibriumor sterically locked into one form by appropriate substitution. It isunderstood that the various tautomeric forms are within the scope of thecompounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

It is understood and appreciated that compounds of Formula Ia andformulae related thereto may have one or more chiral centers andtherefore can exist as enantiomers and/or diastereoisomers. Theinvention is understood to extend to and embrace all such enantiomers,diastereoisomers and mixtures thereof, including but not limited toracemates. It is understood that compounds of Formula Ia and formulaeused throughout this disclosure are intended to represent all individualenantiomers and mixtures thereof, unless stated or shown otherwise.

It is understood and appreciated that compounds of Formula Ia exist asmeso isomers. Such meso isomers may be referred to as cis and trans.Certain cis meso isomers of compounds of Formula Ia are named hereinusing the prefix (1s,4s) and certain trans meso isomers of compounds ofFormula Ia are named herein using the prefix (1r,4r) as shown below.

The Group R¹:

In some embodiments, R¹ is selected from: H and C₁-C₆ alkyl.

In some embodiments, R¹ is H.

In some embodiments, R¹ is C₁-C₆ alkyl.

In some embodiments, R¹ is tert-butyl.

The Group R²:

In some embodiments, R² is selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈haloalkyl and halogen.

In some embodiments, R² is selected from: C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈haloalkyl and halogen.

In some embodiments, R² is selected from: C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: chloro, ethyl, fluoro, isopropyl, methoxy, methyl,methylthio, phenyl and trifluoromethyl.

In some embodiments, R² is selected from: methyl, phenyl, pyridinyl,thiophen-2-yl and thiophen-3-yl; wherein said methyl, phenyl, pyridinyl,thiophen-2-yl and thiophen-3-yl are each optionally substituted with oneor more substituents each independently selected from: chloro, ethyl,fluoro, isopropyl, methoxy, methyl, methylthio, phenyl andtrifluoromethyl.

In some embodiments, R² is selected from: 2,3-difluorophenyl,2-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluorophenyl,2-methoxyphenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl,4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,4-ethylphenyl, 4-fluorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,5-methylpyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,benzhydryl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yland thiophen-3-yl.

In some embodiments, R² is 2,3-difluorophenyl.

In some embodiments, R² is 2-chlorophenyl.

In some embodiments, R² is 2-fluoro-4-methylphenyl.

In some embodiments, R² is 2-fluorophenyl.

In some embodiments, R² is 2-methoxyphenyl.

In some embodiments, R² is 3-chlorophenyl.

In some embodiments, R² is 3-fluoro-4-methylphenyl.

In some embodiments, R² is 3-fluoro-5-methoxyphenyl.

In some embodiments, R² is 3-fluorophenyl.

In some embodiments, R² is 3-methoxyphenyl.

In some embodiments, R² is 4-(methylthio)phenyl.

In some embodiments, R² is 4-(trifluoromethyl)phenyl.

In some embodiments, R² is 4-chloro-2-fluorophenyl.

In some embodiments, R² is 4-chloro-3-fluorophenyl.

In some embodiments, R² is 4-chlorophenyl.

In some embodiments, R² is 4-ethylphenyl.

In some embodiments, R² is 4-fluorophenyl.

In some embodiments, R² is 4-isopropylphenyl.

In some embodiments, R² is 4-methoxyphenyl.

In some embodiments, R² is 5-methylpyridin-3-yl.

In some embodiments, R² is 6-chloropyridin-3-yl.

In some embodiments, R² is 6-methylpyridin-3-yl.

In some embodiments, R² is benzhydryl.

In some embodiments, R² is phenyl.

In some embodiments, R² is p-tolyl.

In some embodiments, R² is pyridin-3-yl.

In some embodiments, R² is pyridin-4-yl.

In some embodiments, R² is thiophen-2-yl.

In some embodiments, R² is thiophen-3-yl.

The Group R³:

In some embodiments, R³ is selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈haloalkyl and halogen.

In some embodiments, R³ is selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy and halogen.

In some embodiments, R³ is selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: chloro, fluoro, methoxy and methyl.

In some embodiments, R³ is selected from: H, 1H-pyrazol-4-yl, phenyl,pyridinyl and thiophen-2-yl; wherein said phenyl, pyridinyl andthiophen-2-yl are each optionally substituted with one or moresubstituents each independently selected from: chloro, fluoro, methoxyand methyl.

In some embodiments, R³ is selected from: H, 1H-pyrazol-4-yl,2,3-difluorophenyl, 2-chlorophenyl, 2-chloropyridin-4-yl,2-fluoro-3-methoxyphenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,3-chlorophenyl, 3-fluoro-5-methoxyphenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl,4-methylthiophen-2-yl, 5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiophen-2-yl, 6-fluoropyridin-3-yl,m-tolyl, phenyl, p-tolyl, pyridin-3-yl, pyridin-4-yl and thiophen-2-yl.

In some embodiments, R³ is H.

In some embodiments, R³ is 1H-pyrazol-4-yl.

In some embodiments, R³ is 2,3-difluorophenyl.

In some embodiments, R³ is 2-chlorophenyl.

In some embodiments, R³ is 2-chloropyridin-4-yl.

In some embodiments, R³ is 2-fluoro-3-methoxyphenyl.

In some embodiments, R³ is 2-fluoropyridin-3-yl.

In some embodiments, R³ is 2-fluoropyridin-4-yl.

In some embodiments, R³ is 2-methoxyphenyl.

In some embodiments, R³ is 2-methylpyridin-4-yl.

In some embodiments, R³ is 3,4-dichlorophenyl.

In some embodiments, R³ is 3,5-dichlorophenyl.

In some embodiments, R³ is 3-chloro-2-fluorophenyl.

In some embodiments, R³ is 3-chloro-4-fluorophenyl.

In some embodiments, R³ is 3-chlorophenyl.

In some embodiments, R³ is 3-fluoro-5-methoxyphenyl.

In some embodiments, R³ is 3-fluorophenyl.

In some embodiments, R³ is 3-methoxyphenyl.

In some embodiments, R³ is 4-chlorophenyl.

In some embodiments, R³ is 4-fluorophenyl.

In some embodiments, R³ is 4-methoxyphenyl.

In some embodiments, R³ is 4-methylthiophen-2-yl.

In some embodiments, R³ is 5-chloro-2-fluorophenyl.

In some embodiments, R³ is 5-chloro-pyridin-3-yl.

In some embodiments, R³ is 5-methylpyridin-3-yl.

In some embodiments, R³ is 5-methylthiophen-2-yl.

In some embodiments, R³ is 6-fluoropyridin-3-yl.

In some embodiments, R³ is m-tolyl.

In some embodiments, R³ is phenyl.

In some embodiments, R³ is p-tolyl.

In some embodiments, R³ is pyridin-3-yl.

In some embodiments, R³ is pyridin-4-yl.

In some embodiments, R³ is thiophen-2-yl.

The Group X:

In some embodiments, X is selected from: N and CH.

In some embodiments, X is N.

In some embodiments, X is CH.

Certain Combinations of the Present Invention:

In some embodiments, R² and R³ are each independently selected from: H,C₁-C₈ alkyl, aryl and heteroaryl; wherein said C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one or more substituentseach independently selected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈alkylthio, aryl, C₁-C₈ haloalkyl and halogen.

In some embodiments, R² and R³ are each independently selected from: H,C₁-C₈ alkyl, aryl and heteroaryl; wherein said C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one, two, three, four orfive substituents each independently selected from: C₁-C₈ alkyl, C₁-C₈alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyl and halogen.

In some embodiments, R² and R³ are each independently selected from: H,C₁-C₈ alkyl, aryl and heteroaryl; wherein said C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one, two, three or foursubstituents each independently selected from: C₁-C₈ alkyl, C₁-C₈alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyl and halogen.

In some embodiments, R² and R³ are each independently selected from: H,C₁-C₈ alkyl, aryl and heteroaryl; wherein said C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one, two or threesubstituents each independently selected from: C₁-C₈ alkyl, C₁-C₈alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyl and halogen.

In some embodiments, R² and R³ are each independently selected from: H,C₁-C₈ alkyl, aryl and heteroaryl; wherein said C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one or two substituentseach independently selected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈alkylthio, aryl, C₁-C₅ haloalkyl and halogen.

In some embodiments, R² and R³ are each independently selected from: H,C₁-C₈ alkyl, aryl and heteroaryl; wherein said C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one substituent selectedfrom: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyland halogen.

In some embodiments, R² and R³ are each independently selected from: H,C₁-C₈ alkyl, aryl and heteroaryl; wherein said C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one or more substituentseach independently selected from: chloro, ethyl, fluoro, isopropyl,methoxy, methyl, methylthio, phenyl and trifluoromethyl.

In some embodiments, R² and R³ are each independently selected from: H,1H-pyrazol-4-yl, methyl, phenyl, pyridinyl, thiophen-2-yl andthiophen-3-yl; wherein said methyl, phenyl, pyridinyl, thiophen-2-yl andthiophen-3-yl are each optionally substituted with one or moresubstituents each independently selected from: chloro, ethyl, fluoro,isopropyl, methoxy, methyl, methylthio, phenyl and trifluoromethyl.

In some embodiments, R² and R³ are each independently selected from: H,1H-pyrazol-4-yl, 2,3-difluorophenyl, 2-chlorophenyl,2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methylphenyl,2-fluorophenyl, 2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 2-methylpyridin-4-yl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl,3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl,4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl,4-isopropylphenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl,5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl,5-methylthiophen-2-yl, 6-chloropyridin-3-yl, 6-fluoropyridin-3-yl,6-methylpyridin-3-yl, benzhydryl, m-tolyl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyl and halogen; and

R³ is selected from: H, C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy and halogen.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ic and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: 2,3-difluorophenyl, 2-chlorophenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl,3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl,4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl,4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl,6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; and

R³ is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl,2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl,5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl,5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl and thiophen-2-yl.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyl and halogen; and

R³ is selected from: H, C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy and halogen.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: 2,3-difluorophenyl, 2-chlorophenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl,3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl,4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl,4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl,6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; and

R³ is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl,2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl,5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl,5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl and thiophen-2-yl.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyl and halogen; and

R³ is selected from: H, C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy and halogen.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ig and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: 2,3-difluorophenyl, 2-chlorophenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl,3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl,4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl,4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl,6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; and

R³ is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl,2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl,5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl,5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl and thiophen-2-yl.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈ haloalkyl and halogen; and

R³ is selected from: H, C₁-C₈ alkyl, aryl and heteroaryl; wherein saidC₁-C₈ alkyl, aryl and heteroaryl are each optionally substituted withone or more substituents each independently selected from: C₁-C₈ alkyl,C₁-C₈ alkoxy and halogen.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula Ii and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R² is selected from: 2,3-difluorophenyl, 2-chlorophenyl,2-fluoro-4-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,3-chlorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl,3-fluorophenyl, 3-methoxyphenyl, 4-(methylthio)phenyl,4-(trifluoromethyl)phenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethylphenyl, 4-fluorophenyl,4-isopropylphenyl, 4-methoxyphenyl, 5-methylpyridin-3-yl,6-chloropyridin-3-yl, 6-methylpyridin-3-yl, benzhydryl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl, thiophen-2-yl and thiophen-3-yl; and

R³ is selected from: H, 1H-pyrazol-4-yl, 2,3-difluorophenyl,2-chlorophenyl, 2-chloropyridin-4-yl, 2-fluoro-3-methoxyphenyl,2-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,2-methylpyridin-4-yl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl,3-fluoro-5-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylthiophen-2-yl,5-chloro-2-fluorophenyl, 5-chloro-pyridin-3-yl, 5-methylpyridin-3-yl,5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, m-tolyl, phenyl, p-tolyl,pyridin-3-yl, pyridin-4-yl and thiophen-2-yl.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group shown in TABLEA.

TABLE A Cpd No. Chemical Structure Chemical Name  1

2-(((1r,4r)-4-((4-(3- methoxyphenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  2

2-(((1s,4s)-4-((4-(3- methoxyphenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  3

2-(((1s,4s)-4-((6-oxo-3,4- diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  4

2-(((1s,4s)-4-((3- benzhydryl-6-oxopyridazin- 1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  5

2-((1s,4s)-4-((3-(4- methoxyphenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  6

2-(((1s,4s)-4-((4-(3- chlorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  7

2-(((1r,4r)-4-((3- benzhydryl-6-oxopyridazin- 1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  8

2-(((1s,4s)-4-((4-(2,3- difluorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid  9

2-(((1s,4s)-4-((6-oxo-3- phenyl-4-m-tolylpyridazin- 1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 10

2-(((1s,4s)-4-((6-oxo-3- phenyl-4-p-tolylpyridazin- 1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 11

2-(((1s,4s)-4-((4-(3- fluorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 12

2-(((1s,4s)-4-((4-(4- fluorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 13

2-(((1s,4s)-4-((4-(2- chlorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 14

2-(((1s,4s)-4-((4-(4- chlorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 15

2-(((1s,4s)-4-((4-(2- methoxyphenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 16

2-(((1s,4s)-4-((4-(4- methoxyphenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 17

2-(((1s,4s)-4-((4-(2-fluoro- 3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 18

2-(((1s,4s)-4-((4-(3-fluoro- 5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 19

2-(((1r,4r)-4-((6-oxo-3,4- diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 20

2-(((1s,4s)-4-((6-oxo-4- phenyl-3-p-tolylpyridazin- 1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 21

2-(((1s,4s)-4-((3-(3- fluorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 22

2-(((1s,4s)-4-((3-(4- fluorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 23

2-(((1s,4s)-4-((3-(2- chlorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 24

2-(((1s,4s)-4-((3-(4- chlorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 25

2-(((1s,4s)-4-((3-(2- methoxyphenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 26

2-(((1s,4s)-4-((3-(3- methoxyphenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 27

2-(((1s,4s)-4-((3-(3-fluoro- 5-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 28

2-(((1s,4s)-4-((3-(2,3- difluorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 29

2-(((1s,4s)-4-((3-(3- chlorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 30

2-(((1s,4s)-4-((4-(5-chloro- 2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 31

2-(((1s,4s,)-4-((4-(3-chloro- 2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 32

2-(((1s,4s)-4-((4-(3-chloro- 4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 33

2-(((1s,4s)-4-((4-(3,5- dichlorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 34

2-(((1s,4s)-4-((4-(3,4- dichlorophenyl)-6-oxo-3- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 35

2-(((1s,4s)-4-((3-(2- fluorophenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 36

2-(((1s,4s)-4-((3-(4- ethylphenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 37

2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(4- (trifluoromethyl)phenyl)pyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 38

2-(((1s,4s)-4-((3-(3-fluoro- 4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 39

2-(((1s,4s)-4-((3-(4- isopropylphenyl)-6-oxo-4- phenylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 40

2-(((1s,4s)-4-((3-(2-fluoro- 4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 41

2-(((1s,4s)-4-((3-(4- (methylthio)phenyl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 42

2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(pyridin-3- yl)pyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 43

2-(((1s,4s)-4-((3-oxo-5,6-di- p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 44

2-(((1s,4s)-4-((6-oxo-3- phenyl-4-(pyridin-3- yl)pyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 45

2-(((1s,4s)-4-((4-(5- methylthiophen-2-yl)-6- oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 46

2-(((1s,4s)-4-((6-oxo-3- phenyl-4-(1H-pyrazol-4- yl)pyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 47

2-(((1s,4s)-4-((4-(3- chlorophenyl)-6-oxo-3-p- tolylpyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 48

2-(((1s,4s)-4-((3-oxo-5,6- diphenyl-1,2,4-triazin- 2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 49

2-(((1s,4s)-4-((5,6-bis(4- fluorophenyl)-3-oxo-1,2,4- triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 50

2-(((1s,4s)-4-((4-(4- methylthiophen-2-yl)-6- oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 51

2-(((1s,4s)-4-((4-(2- methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 52

2-(((1s,4s)-4-((3-(4-chloro- 2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 53

2-(((1s,4s)-4-((3-(4-chloro- 3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 54

2-(((1s,4s)-4-((4-(2- fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 55

2-(((1s,4s)-4-((4-(6- fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 56

2-(((1s,4s)-4-((4-(2- chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 57

2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(pyridin-4- yl)pyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 58

2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(thiophen-2- yl)pyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 59

2-(((1s,4s)-4-((4-(2- fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 60

2-(((1s,4s)-4-((4-(5- methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 61

2-(((1s,4s)-4-((6-oxo-4- phenyl-3-(thiophen-3- yl)pyridazin-1(6H)-yl)methyl)cyclohexyl) methoxy)acetic acid 62

2-(((1s,4s)-4-((3-(5- rnethylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 63

2-(((1s,4s)-4-((3-(6- methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 64

2-((1s,4s)-4-((6-(4- fluorophenyl)-3-oxo-5- phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 65

2-(((1s,4s)-4-((3-(6- chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 66

2-(((1s,4s)-4-((4-(5- chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)- yl)methyl)cyclohexyl) methoxy)acetic acid 67

2-(((1s,4s)-4-((5-(3- chlorophenyl)-3-oxo-6- phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 68

2-(((1s,4s)-4-((3-oxo-5- phenyl-6-p-tolyl-1,2,4- triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 69

2-(((1s,4s)-4-((6-(4- methoxyphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic acid 70

2-((1s,4s)-4-((5-(3- methoxyphenyl)-3-oxo-6- phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 71

2-(((1s,4s)-4-((6-(2-fluoro- 4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic acid 72

2-(((1s,4s)-4-((6-(4- chlorophenyl)-3-oxo-5- phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 73

2-(((1s,4s)-4-((3-oxo-6- phenyl-5-m-tolyl-1,2,4- triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 74

2-(((1s,4s)-4-((5-(3- fluorophenyl)-3-oxo-6- phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 75

2-(((1r,4r)-4-((6-(2-fluoro- 4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic acid 76

2-(((1r,4r)-4-((3-oxo-5- phenyl-6-p-tolyl-1,2,4- triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 77

2-(((1s,4s)-4-((3-oxo-6- phenyl-5-(pyridin-3-yl)- 1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 78

2-(((1s,4s)-4-((3-oxo-6- (pyridin-3-yl)-5-p-tolyl- 1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 79

2-(((1s,4s)-4-((3-oxo-5- (pyridin-4-yl)-6-p-tolyl- 1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 80

2-(((1s,4s)-4-((3-oxo-5-m- tolyl-6-p-tolyl-1,2,4-triazin- 2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 81

2-(((1r,4r)-4-((3-oxo-6- phenyl-5-m-tolyl-1,2,4- triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 82

2-(((1r,4r)-4-((5-(3- fluorophenyl)-3-oxo-6- phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 83

2-(((1r,4r)-4-((3-oxo-5-m- tolyl-6-p-tolyl-1,2,4-triazin- 2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 84

2-(((1s,4s)-4-((3-oxo-6- phenyl-5-(thiophen-2-yl)- 1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetic acid 85

2-(((1s,4s)-4-((5-(3- chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)- yl)methyl)cyclohexyl) methoxy)acetic acid 86

2-(2-(((1s,4s)-4-((3-oxo-5- phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl) cyclohexyl)methoxy) acetamido) acetic acid 87

2-(2-(((1s,4s)-4-((3-oxo-5- phenyl-6-p-tolyl- 1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl) methoxy)acetamido) ethanesulfonic acid

Additionally, individual compounds and chemical genera of the presentinvention, for example those compounds found in TABLE A includingdiastereoisomers and enantiomers thereof, encompass all pharmaceuticallyacceptable salts, solvates and particularly hydrates, thereof.

The compounds of the Formula Ia of the present invention may be preparedaccording to relevant published literature procedures that are used byone skilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter in the working Examples. Protection anddeprotection may be carried out by procedures generally known in the art(see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groupsin Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]; incorporated hereinby reference in its entirety).

It is understood that the present invention embraces eachdiastereoisomer, each enantiomer and mixtures thereof of each compoundand generic formulae disclosed herein just as if they were eachindividually disclosed with the specific stereochemical designation foreach chiral carbon. Separation of the individual isomers (such as, bychiral HPLC, recrystallization of diastereoisomeric mixtures and thelike) or selective synthesis (such as, by enantiomeric selectivesyntheses and the like) of the individual isomers is accomplished byapplication of various methods which are well known to practitioners inthe art.

Indications and Methods of Prophylaxis and/or Treatment

In addition to the foregoing beneficial uses for the modulators of PGI2receptor activity disclosed herein, the compounds disclosed herein areuseful in the treatment of several additional diseases and disorders,and in the amelioration of symptoms thereof. Without limitation, theseinclude the following:

1. Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology.Vasoconstriction, remodeling of the pulmonary vessel wall, andthrombosis contribute to increased pulmonary vascular resistance in PAH(Humbert et al., J. Am. Coll. Cardiol., 2004, 43:13S-24S.)

The compounds of the present invention disclosed herein are useful inthe treatment of pulmonary arterial hypertension (PAH) and symptomsthereof. PAH shall be understood to encompass the following forms ofpulmonary arterial hypertension described in the 2003 World HealthOrganization (WHO) clinical classification of pulmonary arterialhypertension: idiopathic PAH (IPAH); familial PAH (FPAH); PAH associatedwith other conditions (APAH), such as PAH associated with collagenvascular disease, PAH associated with congenital systemic-to-pulmonaryshunts, PAH associated with portal hypertension, PAH associated with HIVinfection, PAH associated with drugs or toxins, or PAH associated withOther; and PAH associated with significant venous or capillaryinvolvement.

Idiopathic PAH refers to PAH of undetermined cause.

Familial PAH refers to PAH for which hereditary transmission issuspected or documented.

PAH associated with collagen vascular disease shall be understood toencompass PAH associated with scleroderma, PAH associated with CREST(calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction,sclerodactyly, and telangiectasias) syndrome, PAH associated withsystemic lupus erythematosus (SLE), PAH associated with rheumatoidarthritis, PAH associated with Takayasu's arteritis, PAH associated withpolymyositis, and PAH associated with dermatomyositis.

PAH associated with congenital systemic-to-pulmonary shunts shall beunderstood to encompass PAH associated with atrial septic defect (ASD),PAH associated with ventricular septic defect (VSD) and PAH associatedwith patent ductus arteriosus.

PAH associated with drugs or toxins shall be understood to encompass PAHassociated with ingestion of aminorex, PAH associated with ingestion ofa fenfluramine compound (e.g., PAH associated with ingestion offenfluramine or PAH associated with ingestion of dexfenfluramine), PAHassociated with ingestion of certain toxic oils (e.g., PAH associatedwith ingestion of rapeseed oil), PAH associated with ingestion ofpyrrolizidine alkaloids (e.g., PAH associated with ingestion of bushtea) and PAH associated with ingestion of monocrotaline.

PAH associated with Other shall be understood to encompass PAHassociated with a thyroid disorder, PAH associated with glycogen storagedisease, PAH associated with Gaucher disease, PAH associated withhereditary hemorrhagic telangiectasia, PAH associated with ahemoglobinopathy, PAH associated with a myeloproliferative disorder, andPAH associated with splenectomy.

PAH associated with significant venous or capillary involvement shall beunderstood to encompass PAH associated with pulmonary veno-occlusivedisease (PVOD) and PAH associated with pulmonary capillaryhemangiomatosis (PCH).

(See, e.g., Simonneau et al., J. Am. Coll. Cardiol., 2004, 43:5S-12S;McGoon et al., Chest, 2004, 126:14S-34S; Rabinovitch, Annu. Rev. Pathol.Mech. Dis., 2007, 2:369-399; McLaughlin et al., Circulation, 2006,114:1417-1431; Strauss et al., Clin. Chest. Med., 2007, 28:127-142;Taichman et al., Clin. Chest. Med., 2007, 28:1-22.)

Evidence for the association of PAH with scleroderma and the beneficialeffect of an agonist of the PGI2 receptor on PAH is given by Badesch etal. (Badesch et al., Ann. Intern. Med., 2000, 132:425-434). Evidence forthe association of PAH with the collagen vascular diseases mixedconnective tissue disease (MCTD), systemic lupus erythematosus (SLE),Sjögren's syndrome and CREST syndrome and the beneficial effect of anagonist of the PGI2 receptor on PAH is given by Humbert et al. (Eur.Respir. J., 1999, 13:1351-1356). Evidence for the association of PAHwith CREST syndrome and the beneficial effect of an agonist of the PGI2receptor on PAH is given by Miwa et al. (Int. Heart J., 2007,48:417-422). Evidence for the association of PAH with SLE and thebeneficial effect of an agonist of the PGI2 receptor on PAH is given byRobbins et al. (Chest, 2000, 117:14-18). Evidence for the association ofPAH with HIV infection and the beneficial of an agonist of the PGI2receptor on PAH is given by Aguilar et al. (Am. J. Respir. Crit. CareMed., 2000, 162:1846-1850). Evidence for the association of PAH withcongenital heart defects (including ASD, VSD and patent ductusarteriosus) and the beneficial effect of an agonist of the PGI2 receptoron PAH is given by Rosenzweig et al. (Circulation, 1999, 99:1858-1865).Evidence for the association of PAH with fenfluramine and withdexfenfluramine, anorexigens, is given by Archer et al. (Am. J. Respir.Crit. Care Med., 1998, 158:1061-1067). Evidence for the association ofPAH with hereditary hemorrhagic telangiectasia is given by McGoon et al.(Chest, 2004, 126:14-34). Evidence for the association of PAH withsplenectomy is given by Hoeper et al. (Ann. Intern. Med., 1999,130:506-509). Evidence for the association of PAH with portalhypertension and the beneficial effect of an agonist of the PGI2receptor on PAH is given by Hoeper et al. (Eur. Respir. J., 2005,25:502-508).

Symptoms of PAH include dyspnea, angina, syncope and edema (McLaughlinet al., Circulation, 2006, 114:1417-1431). The compounds of the presentinvention disclosed herein are useful in the treatment of symptoms ofPAH.

Tawara et al. have demonstrated that long-term inhibition of Rho-kinase,an effector of the small GTPase Rho, ameliorates monocrotaline-inducedPAH in rats and hypoxia-induced PAH in mice. The same group alsoreported that prostacyclin and its oral analog, beraprost sodium (BPS),may lack direct inhibitory effect on Rho-kinase in vitro, suggestingthat combination therapy with a Rho-kinase inhibitor and BPS iseffective for the treatment of PAH. Thus, male Sprague-Dawley rats weregiven a s.c. injection of monocrotaline (60 mg/kg) and maintained withor without the treatment with a Rho-kinase inhibitor, fasudil (30mg/kg/day), BPS (200 μg/kg/day), or a combination of both drugs forthree weeks. The combination therapy, when compared with eachmonotherapy, showed significantly more improvement in PAH, rightventricular hypertrophy, and pulmonary medial thickness without anyadverse effects. (See, Tawara et al., Journal of CardiovascularPharmacology (2007), 50(2), 195-200.)

The PGI2 receptor agonists disclosed herein, alone or in combinationwith a Rho-kinase inhibitor, are useful in the treatment of pulmonaryarterial hypertension (PAH) and symptoms thereof.

The enzyme tryptophan hydroxylase (TPH), has two known isoforms: TPH1,which is expressed in the periphery, and TPH2, which is expressedprimarily in the brain. Mice genetically deficient for the TPH1 gene(“knockout mice”) have been reported. In one case, the mice reportedlyexpressed normal amounts of serotonin in classical serotonergic brainregions, but largely lacked serotonin in the periphery. Walther, D. J.,et al., Science 299:76 (2003). In another, the knockout mice exhibitedabnormal cardiac activity, which was attributed to a lack of peripheralserotonin. Cote, F., et al., PNAS 100(23):13525-13530 (2003).

Recently, TPH knockout mice were studied in a hypoxia-induced pulmonaryarterial hypertension model. Morecroft, I., et al., Hypertension49:232-236 (2007). The results of those studies suggest that TPH1 andperipheral serotonin play an essential role in the development ofhypoxia-induced elevations in pulmonary pressures and hypoxia-inducedpulmonary vascular remodeling.

The PGI2 receptor agonists disclosed herein, alone or in combinationwith a tryptophan hydroxylase inhibitor, are useful in the treatment ofpulmonary arterial hypertension (PAH) and symptoms thereof.

2. Antiplatelet Therapies (Conditions Related to Platelet Aggregation)

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who are at riskof developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction (“MI” or “heart attack”), the heart muscledoes not receive enough oxygen-rich blood as a result of a blockage inthe coronary blood vessels. If taken while an attack is in progress orimmediately afterward (preferably within 30 min), antiplatelets canreduce the damage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure ordiscomfort caused by inadequate oxygen-rich blood flow (ischemia) tosome parts of the heart. In patients with angina, antiplatelet therapycan reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes.

Angioplasty is a catheter based technique used to open arteriesobstructed by a blood clot. Whether or not stenting is performedimmediately after this procedure to keep the artery open, antiplateletscan reduce the risk of forming additional blood clots following theprocedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrhythmia). Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

There is evidence that a PGI2 receptor agonist will inhibit plateletaggregation and thus be a potential treatment as an antiplatelet therapy(see, e.g., Moncada et al., Lancet, 1977, 1:18-20). It has been shownthat genetic deficiency of the PGI2 receptor in mice leads to anincreased propensity towards thrombosis (Murata et al., Nature, 1997,388:678-682).

PGI2 receptor agonists can be used to treat, for example, claudicationor peripheral artery disease as well as cardiovascular complications,arterial thrombosis, atherosclerosis, vasoconstriction caused byserotonin, ischemia-reperfusion injury, and restenosis of arteriesfollowing angioplasty or stent placement. (See, e.g., Fetalvero et al.,Prostaglandins Other Lipid Mediat., 2007, 82:109-118; Arehart et al.,Curr. Med. Chem., 2007, 14:2161-2169; Davi et al., N. Engl. J. Med.,2007, 357:2482-2494; Fetalvero et al., Am. J. Physiol. Heart. Circ.Physiol., 2006, 290:H1337-H1346; Murata et al., Nature, 1997,388:678-682; Wang et al., Proc. Natl. Acad. Sci. USA, 2006,103:14507-14512; Xiao et al., Circulation, 2001, 104:2210-2215;McCormick et al., Biochem. Soc. Trans., 2007, 35:910-911; Arehart etal., Circ. Res., 2008, 102(8), 986-93.)

PGI2 receptor agonists can also be used alone or in combination withthrombolytic therapy, for example, tissue-type plasminogen activator(t-PA), to provide cardioprotection following MI or postischemicmyocardial dysfunction or protection from ischemic injury duringpercutaneous coronary intervention, and the like, includingcomplications resulting therefrom. PGI2 receptor agonists can also beused in antiplatelet therapies in combination with, for example,alpha-tocopherol (vitamin E), echistatin (a disintegrin) or, in statesof hypercoagulability, heparin. (See, e.g., Chan., J. Nutr., 1998,128:1593-1596; Mardla et al., Platelets, 2004, 15:319-324; Bernabei etal., Ann. Thorac. Surg., 1995, 59:149-153; Gainza et al., J. Nephrol.,2006, 19:648-655.)

The PGI2 receptor agonists disclosed herein provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove. Accordingly, in some embodiments, the present invention providesmethods for reducing platelet aggregation in a patient in need thereof,comprising administering to the patient a composition comprising a PGI2receptor agonist disclosed herein. In further embodiments, the presentinvention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising a PGI2receptor agonist disclosed herein at a time where such risk exists.

3. Atherosclerosis

Atherosclerosis is a complex disease characterized by inflammation,lipid accumulation, cell death and fibrosis. It is the leading cause ofmortality in many countries, including the United States.Atherosclerosis, as the term is used herein, shall be understood toencompass disorders of large and medium-sized arteries that result inthe progressive accumulation within the intima of smooth muscle cellsand lipids.

It has been shown that an agonist of the PGI2 receptor can conferprotection from atherosclerosis, such as from atherothrombosis (Arehartet al., Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al.,Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et al.,Hematology Am. Soc. Hematol. Educ. Program, 2005:445-451; Egan et al.,Science, 2004, 306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004,114:784-794; Arehart et al., Circ. Res., 2008, 102(8), 986-93).

It has been shown that defective PGI2 receptor signaling appears toaccelerate atherothrombosis in humans, i.e. that an agonist of the PGI2receptor can confer protection from atherothrombosis in humans (Arehartet al., Circ. Res., 2008, 102(8), 986-93).

The compounds of the present invention disclosed herein are useful inthe treatment of atherosclerosis, and the treatment of the symptomsthereof. Accordingly, in some embodiments, the present inventionprovides methods for treating atherosclerosis in a patient in need ofthe treatment, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein. In furtherembodiments, methods are provided for treating a symptom ofatherosclerosis in a patient in need of the treatment, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein.

4. Asthma

Asthma is a lymphocyte-mediated inflammatory airway disordercharacterized by airway eosinophilia, increased mucus production bygoblet cells, and structural remodeling of the airway wall. Theprevalence of asthma has dramatically increased worldwide in recentdecades. It has been shown that genetic deficiency of the PGI2 receptorin mice augments allergic airway inflammation (Takahashi et al., Br JPharmacol, 2002, 137:315-322). It has been shown that an agonist of thePGI2 receptor can suppress not only the development of asthma when givenduring the sensitization phase, but also the cardinal features ofexperimental asthma when given during the challenge phase (Idzko et al.,J. Clin. Invest., 2007, 117:464-472; Nagao et al., Am. J. Respir. CellMol. Biol., 2003, 29:314-320), at least in part through markedlyinterfering with the function of antigen-presenting dendritic cellswithin the airways (Idzko et al., J. Clin. Invest., 2007, 117:464-472;Zhou et al., J. Immunol., 2007, 178:702-710; Jaffar et al., J. Immunol.,2007, 179:6193-6203; Jozefowski et al., Int. Immunopharmacol., 2003,3:865-878). These cells are crucial for both the initiation and themaintenance phases of allergic asthma, as depletion of airway dendriticcells during secondary challenge in sensitized mice abolished allcharacteristic features of asthma, an effect that could be completelyrestored by adoptive transfer of wild-type dendritic cells (van Rijt etal., J. Exp. Med., 2005, 201:981-991). It has also been shown that anagonist of the PGI2 receptor can inhibit proinflammatory cytokinesecretion by human alveolar macrophages (Raychaudhuri et al., J. Biol.Chem., 2002, 277:33344-33348). The compounds of the present inventiondisclosed herein are useful in the treatment of asthma, and thetreatment of the symptoms thereof. Accordingly, in some embodiments, thepresent invention provides methods for treating asthma in a patient inneed of the treatment, comprising administering to the patient acomposition comprising a PGI2 receptor agonist disclosed herein. Infurther embodiments, methods are provided for treating a symptom ofasthma in a patient in need of the treatment, comprising administeringto the patient a composition comprising a PGI2 receptor agonistdisclosed herein.

5. Diabetic-Related Pathologies

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), enhancedvasoconstriction and platelet aggregation in diabetic patients has alsobeen implicated to play a role in disease progression (Cameron et al.,Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367:607-614). Agonists ofthe PGI2 receptor promote vasodilation and inhibit platelet aggregation.Improving microvascular blood flow is able to benefit diabeticcomplications (Cameron, Diabetologia, 2001, 44:1973-1988).

It has been shown that an agonist of the PGI2 receptor can prevent andreverse motor and sensory peripheral nerve conduction abnormalities instreptozotocin-diabetic rats (Cotter et al., Naunyn Schmiedebergs Arch.Pharmacol., 1993, 347:534-540). Further evidence for the beneficialeffect of an agonist of the PGI2 receptor in the treatment of diabeticperipheral neuropathy is given by Hotta et al. (Diabetes, 1996,45:361-366), Ueno et al. (Jpn. J. Pharmacol., 1996, 70:177-182), Ueno etal. (Life Sci., 1996, 59:PL105-PL110), Hotta et al. (Prostaglandins,1995, 49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okudaet al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB J.,2003, 17:779-781). Evidence for the beneficial effect of an agonist ofthe PGI2 receptor in the treatment of diabetic nephropathy is given byOwada et al. (Nephron, 2002, 92:788-796) and Yamashita et al. (DiabetesRes. Clin. Pract., 2002, 57:149-161). Evidence for the beneficial effectof an agonist of the PGI2 receptor in the treatment of diabeticretinopathy is given by Yamagishi et al. (Mol. Med., 2002, 8:546-550),Burnette et al. (Exp. Eye Res., 2006, 83:1359-1365), and Hotta et al.(Diabetes, 1996, 45:361-366). It has been shown that an agonist of thePGI2 receptor can reduce increased tumor necrosis factor-α (TNF-α)levels in diabetic patients, implying that an agonist of the PGI2receptor may contribute to the prevention of progression in diabeticcomplications (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004,112:390-394).

6. Glaucoma

Evidence that topical administration of an agonist of the PGI2 receptorcan result in a decrease in intraocular pressure (IOP) in rabbits anddogs and thereby have beneficial effect in the treatment of glaucoma isgiven by Hoyng et al. (Hoyng et al., Invest. Ophthalmol. Vis. Sci.,1987, 28:470-476).

7. Hypertension

Agonists of the PGI2 receptor have been shown to have activity forregulation of vascular tone, for vasodilation, and for amelioration ofpulmonary hypertension (see, e.g., Strauss et al., Clin Chest Med, 2007,28:127-142; Driscoll et al., Expert Opin. Pharmacother., 2008, 9:65-81).Evidence for a beneficial effect of an agonist of the PGI2 receptor inthe treatment of hypertension is given by Yamada et al. (Peptides, 2008,29:412-418). Evidence that an agonist of the PGI2 receptor can protectagainst cerebral ischemia is given by Dogan et al. (Gen. Pharmacol.,1996, 27:1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab., 2006,26:491-501).

8. Anti-Inflammation Therapies

Anti-inflammation agents are prescribed for a variety of conditions. Forexample, in an inflammatory disease they are used to interfere with andthereby reduce an underlying deleterious There is evidence that a PGI2receptor agonist can inhibit inflammation and thus be a potentialtreatment as an anti-inflammation therapy. It has been shown that anagonist of the PGI2 receptor can inhibit pro-inflammatory cytokine andchemokine (interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α),IL-la, IL-6, macrophage inflammatory protein-1alpha (MIP-la), monocytechemoattractant protein-1 (MCP-1)) production and T cell stimulatoryfunction of dendritic cells (Jozefowski et al., Int. Immunopharmacol.,2003, 865-878; Zhou et al., J. Immunol., 2007, 178:702-710; Nagao etal., Am. J. Respir. Cell Mol. Biol., 2003, 29:314-320; Idzko et al., J.Clin. Invest., 2007, 117:464-472). It has been shown that an agonist ofthe PGI2 receptor can inhibit pro-inflammatory cytokine (TNF-α, IL-1I,IL-6, granulocyte macrophage stimulating factor (GM-CSF)) production bymacrophages (Raychaudhuri et al., J. Biol. Chem., 2002, 277:33344-33348;Czeslick et al., Eur. J. Clin. Invest., 2003, 33:1013-1017; Di Renzo etal., Prostaglandin Leukot. Essent. Fatty Acids, 2005, 73:405-410;Shinomiya et al., Biochem. Pharmacol., 2001, 61:1153-1160). It has beenshown that an agonist of the PGI2 receptor can stimulateanti-inflammatory cytokine (IL-10) production by dendritic cells(Jozefowski et al., Int. Immunopharmacol., 2003, 865-878; Zhou et al.,J. Immunol., 2007, 178:702-710). It has been shown that an agonist ofthe PGI2 receptor can stimulate anti-inflammatory cytokine (IL-10)production by macrophages (Shinomiya et al., Biochem. Pharmacol., 2001,61:1153-1160). It has been shown that an agonist of the PGI2 receptorcan inhibit a chemokine (CCL 17)-induced chemotaxis of leukocytes(CD4⁺Th2 T cells) (Jaffar et al., J. Immunol., 2007, 179:6193-6203). Ithas been shown that an agonist of the PGI2 receptor can conferprotection from atherosclerosis, such as from atherothrombosis (Arehartet al., Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al.,Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et al.,Hematology Am. Soc. Hematol. Educ. Program, 2005:445-451; Egan et al.,Science, 2004, 306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004,114:784-794; Arehart et al., Circ. Res., 2008, 102(8), 986-93). It hasbeen shown that an agonist of the PGI2 receptor can attenuate asthma(Idzko et al., J. Clin. Invest., 2007, 117:464-472; Jaffar et al., J.Immunol., 2007, 179:6193-6203; Nagao et al., Am. J. Respir. Cell. Mol.Biol., 2003, 29:314-320). It has been shown that an agonist of the PGI2receptor can decrease TNF-α production in type 2 diabetes patients(Fujiwara et al., Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394;Goya et al., Metabolism, 2003, 52:192-198). It has been shown that anagonist of the PGI2 receptor can inhibit ischemia-reperfusion injury(Xiao et al., Circulation, 2001, 104:2210-2215). It has been shown thatan agonist of the PGI2 receptor can inhibit restenosis (Cheng et al.,Science, 2002, 296:539-541). It has been shown that an agonist of thePGI2 receptor can attenuate pulmonary vascular injury and shock in a ratmodel of septic shock (Harada et al., Shock, 2008, February 21 Epubahead of print). It has been shown that an agonist of the PGI2 receptorcan reduce the serum levels of TNF-α in vivo in patients with rheumatoidarthritis, and this is associated with improvement in the clinicalcourse of the disease (Gao et al., Rheumatol. Int., 2002, 22:45-51;Boehme et al., Rheumatol. Int., 2006, 26:340-347).

The compounds of the present invention disclosed herein providebeneficial reduction of inflammation. The compounds of the presentinvention disclosed herein provide beneficial reduction of a deleteriousinflammatory response associated with an inflammatory disease.Accordingly, in some embodiments, the present invention provides methodsfor reducing inflammation in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for decreasing IL-12, TNF-α, IL-1α, IL-1β, IL-6, MIP-laor MCP-1 production in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for decreasing TNF-α production in a patient in needthereof, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein. In someembodiments, the present invention provides methods for increasing IL-10production in a patient in need thereof, comprising administering to thepatient a composition comprising a PGI2 receptor agonist disclosedherein. In some embodiments, the present invention provides methods forreducing a deleterious inflammatory response associated with aninflammatory disease in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for treating an inflammatory disease or a symptomthereof in a patient in need of the treatment comprising administeringto the patient a composition comprising a PGI2 receptor agonistdisclosed herein. In some embodiments, the present invention providesmethods for treating an inflammatory disease or a symptom thereof in apatient in need of the treatment comprising administering to the patienta composition comprising a PGI2 receptor agonist disclosed herein. Insome embodiments, the present invention provides methods for treating aninflammatory disease or a symptom thereof in a patient in need of thetreatment comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein, wherein theinflammatory disease is selected from the group consisting of psoriasis,psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplantrejection, multiple sclerosis, systemic lupus erythematosus (SLE),ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, diabetes (including type 1 diabetes and type 2diabetes), sepsis, chronic obstructive pulmonary disease (COPD), andasthma.

9. Traumatic Brain Injury

Prostacyclin production is known to increase after brain trauma, and ina recent study, the importance of prostacyclin for posttraumatichemodynamic alterations and neuron survival was investigated.Prostacyclin receptor-deficient (IP^(−/−)) mice were compared to micewith functional prostacyclin receptors (IP^(+/+)) after a controlledcortical injury. Contusion volume was increased in IP^(−/−) micecompared with IP^(+/+) mice. Three hours after trauma, cortical bloodflow was decreased in the injured cortex of both groups and thereduction in blood flow in the cortex of the IP^(−/−) mice persistedfrom 3 to 24 h, whereas blood flow approached normal values in theIP^(+/+) mice after 24 h. (See, e.g., Lundblad et al. Journal ofCerebral Blood Flow & Metabolism (2008) 28, 367-376).

The PGI2 receptor agonists disclosed herein provide beneficialimprovement in neuron survival after brain trauma. Accordingly, in someembodiments, the present invention provides methods for treating atraumatic brain injury in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.)

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may, in an alternative use, be administered asa raw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with minimal degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate, hydrate orphysiologically functional derivative thereof can be used as activeingredients in pharmaceutical compositions, specifically as PGI2receptor modulators. By the term “active ingredient” is defined in thecontext of a “pharmaceutical composition” and is intended to mean acomponent of a pharmaceutical composition that provides the primarypharmacological effect, as opposed to an “inactive ingredient” whichwould generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits and as is customary and is known to the physician, itis to be tailored to the individual conditions in each individual case.It depends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about25 mg. Multiple doses may be administered during the day, especiallywhen relatively large amounts are deemed to be needed, for example 2, 3or 4 doses. Depending on the individual and as deemed appropriate fromthe patient's physician or caregiver it may be necessary to deviateupward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4 part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt, solvate or hydrate of a compound ofthe invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size. The powders and tablets may contain varyingpercentage amounts of the active compound. A representative amount in apowder or tablet may contain from 0.5 to about 90 percent of the activecompound; however, an artisan would know when amounts outside of thisrange are necessary. Suitable carriers for powders and tablets aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and othersand, if appropriate, customary propellants, for example include carbondioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane,or dichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like. Certain compounds ofthe present invention which contain a carboxylic acid functional groupmay optionally exist as pharmaceutically acceptable salts containingnon-toxic, pharmaceutically acceptable metal cations and cations derivedfrom organic bases. Representative metals include, but are not limitedto, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc andthe like. In some embodiments the pharmaceutically acceptable metal issodium. Representative organic bases include, but are not limited to,benzathine (N¹,N²-dibenzylethane-1,2-diamine), chloroprocaine(2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,diethanolamine, ethylenediamine, meglumine((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine(2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certainpharmaceutically acceptable salts are listed in Berge, et al., Journalof Pharmaceutical Sciences, 66:1-19 (1977), incorporated herein byreference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when the PGI2 receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as PGI2receptor modulators, for the treatment of an PGI2-associated disease ordisorder in companionship animals (e.g., cats, dogs, etc.) and inlivestock animals (e.g., cows, chickens, fish, etc.) Those of ordinaryskill in the art are readily credited with understanding the utility ofsuch compounds in such settings.

Hydrates and Solvates

It is understood that when the phrase pharmaceutically acceptable salts,solvates and hydrates is used in referring to a particular formulaherein, it is intended to embrace solvates and/or hydrates of compoundsof the particular formula, pharmaceutically acceptable salts ofcompounds of the particular formula as well as solvates and/or hydratesof pharmaceutically acceptable salts of compounds of the particularformula.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be apparent tothose skilled in the art that the following dosage forms may comprise,as the active component, either a compound of the invention or apharmaceutically acceptable salt or as a solvate or hydrate thereof.Moreover, various hydrates and solvates of the compounds of theinvention and their salts will find use as intermediates in themanufacture of pharmaceutical compositions. Typical procedures formaking and identifying suitable hydrates and solvates, outside thosementioned herein, are well known to those in the art; see for example,pages 202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc., New York,1999, incorporated herein by reference in its entirety. Accordingly, oneaspect of the present invention pertains to hydrates and solvates ofcompounds of Formula Ia and/or their pharmaceutical acceptable salts, asdescribed herein, that can be isolated and characterized by methodsknown in the art, such as, thermogravimetric analysis (TGA), TGA-massspectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction(XRPD), Karl Fisher titration, high resolution X-ray diffraction, andthe like. There are several commercial entities that provide quick andefficient services for identifying solvates and hydrates on a routinebasis. Example companies offering these services include WilmingtonPharmaTech (Wilmington, Del.), Avantium Technologies (Amsterdam) andAptuit (Greenwich, Conn.).

Pro-Drugs of the Present Invention

The compounds of Formula Ia may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the Formula Ia. Pro-drugs of the present invention mayemploy any pro-drug strategy known in the art. A pro-drug may be used toalter or improve the physical and/or pharmacokinetic profile of theparent compound and can be formed when the parent compound contains asuitable group or substituent which can be derivatized to form apro-drug. Examples of pro-drugs include in-vivo hydrolyzable amides of acompound of the Formula Ia or pharmaceutically-acceptable salts thereof.

One aspect of the present invention pertains to compounds of Formula IIuseful as pro-drugs for the delivery of compounds of Formula Ia:

wherein:

R² and R³ are each independently selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈haloalkyl and halogen;

X is selected from: N and CH.; and

R⁴ is a radical derived from any natural or unnatural amino acid, uponthe loss of a hydrogen atom from the α-amino group of said natural orunnatural amino acid; or

R⁴ is —NHCH₂CH₂SO₃H.

One aspect of the present invention pertains to compounds of Formula IIauseful as pro-drugs for the delivery of compounds of Formula Ia:

wherein:

R² and R³ are each independently selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, aryl, C₁-C₈haloalkyl and halogen;

R⁵ is selected from: H and carboxyl; and

R⁶ is selected from: H and C₁-C₆ alkyl; wherein C₁-C₆ alkyl isoptionally substituted with 4-hydroxyphenyl, amino, carboxamide,carboxyl, guanidino, hydroxyl, imidazolyl, indolyl, methylthio, phenyl,pyrrolidinyl, sulfo and thiol.

In some embodiments, R² is selected from: C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkylthio, aryl, C₁-C₅haloalkyl and halogen.

In some embodiments, R² is aryl optionally substituted with one or moreC₁-C₈ alkyl substituents.

In some embodiments, R² is p-tolyl.

In some embodiments, R³ is selected from: H, C₁-C₈ alkyl, aryl andheteroaryl; wherein said C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents each independentlyselected from: C₁-C₈ alkyl, C₁-C₈ alkoxy and halogen.

In some embodiments, R³ is phenyl.

In some embodiments, R⁵ is H; and R⁶ is —CH₂SO₃H.

In some embodiments, R⁵ is carboxyl; and R⁶ is H.

In some embodiments: R² is p-tolyl; R³ is phenyl; R⁵ is H; and R⁶ is—CH₂SO₃H.

In some embodiments: R² is p-tolyl; R³ is phenyl; R⁵ is carboxyl; and R⁵is H.

Certain pro-drugs of compounds of the present invention are described inExamples 1.88 and 1.89.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the PGI2 receptor in tissue samples,including human and for identifying PGI2 receptor ligands by inhibitionbinding of a radio-labeled compound. It is a further object of thisinvention to develop novel PGI2 receptor assays of which comprise suchradio-labeled compounds.

The present invention embraces isotopically-labeled compounds of thepresent invention. Isotopically or radio-labeled compounds are thosewhich are identical to compounds disclosed herein, but for the fact thatone or more atoms are replaced or substituted by an atom having anatomic mass or mass number different from the atomic mass or mass numbermost commonly found in nature. Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ²H (also written as D for deuterium), ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. For example,for in vitro PGI2 receptor labeling and competition assays, compoundsthat incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S will generally be mostuseful. For radio-imaging applications ¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula Ia, Ic, Ie, Ig, or Ii that has incorporated at leastone radionuclide; in some embodiments the radionuclide is selected fromthe group consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or 14C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Drawings and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the scarcer radio-isotope or nonradioactiveisotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas: This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]: This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with Lithium Aluminum Hydride [³H]: This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters and the like.

D. Tritium Gas Exposure Labeling: This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]: This procedure is usuallyemployed to prepare O-methyl or N-methyl (3H) products by treatingappropriate precursors with high specific activity methyl iodide (3H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions: This procedure transforms an aryl amineor a heteroaryl amine into a diazonium salt, such as a diazoniumtetrafluoroborate salt and subsequently to ¹²⁵I labeled compound usingNa¹²⁵I. A represented procedure was reported by Zhu, G-D. and co-workersin J. Org. Chem., 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols: This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999,42, S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I: This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresentative procedure was reported by Le Bas, M.-D. and co-workers inJ. Labelled Compd. Radiopharm. 2001, 44, S280-S282.

A radiolabeled PGI2 receptor compound of Formula Ia can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula Ia” to the PGI2 receptor. Accordingly, the abilityof a test compound to compete with the “radio-labeled compound ofFormula Ia” for the binding to the PGI2 receptor directly correlates toits binding affinity.

The labeled compounds of the present invention bind to the PGI2receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those skilled in the art based upon, inter alia, a review of thisdisclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1: Syntheses of Compounds of the Present Invention

Illustrated syntheses for compounds of the present invention are shownin FIGS. 2 through 6 where the symbols have the same definitions as usedthroughout this disclosure.

The compounds of the invention and their syntheses are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to the CS ChemDraw UltraVersion 7.0.1, AutoNom version 2.2, or CS ChemDraw Ultra Version 9.0.7.In certain instances common names are used and it is understood thatthese common names would be recognized by those skilled in the art.

Chemistry:

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on aBruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI(Broad Band Inverse) and z-gradient. Chemical shifts are given in partsper million (ppm) with the residual solvent signal used as reference.NMR abbreviations are used as follows: s=singlet, d=doublet, dd=doubletof doublets, ddd=doublet of doublet of doublets, dt=doublet of triplets,t=triplet, td=triplet of doublets, tt=triplet of triplets, q=quartet,m=multiplet, bs=broad singlet, bt=broad triplet. Microwave irradiationswere carried out using a Smith Synthesizer™ or an Emrys Optimizer™(Biotage). Thin-layer chromatography (TLC) was performed on silica gel60 F₂₅₄ (Merck), preparatory thin-layer chromatography (prep TLC) waspreformed on PK6F silica gel 60 A 1 mm plates (Whatman) and columnchromatography was carried out on a silica gel column using Kieselgel60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressureon a Biichi rotary evaporator.

LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.

Example 1.1: Preparation of2-(((1s,4s)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 68) and Sodium Salt Thereof Step A: Preparation of2-(Hydroxyimino)-2-phenyl-1-p-tolylethanone

To a solution of 2-phenyl-1-p-tolylethanone (5.0 g, 23.78 mmol) in EtOH(475.0 mL) at room temperature was added dropwise tert-butyl nitrite(5.5 mL, 46.2 mmol) followed by sodium ethoxide (4.07 g, 59.8 mmol). Thereaction was stirred at room temperature overnight and concentratedunder reduced pressure. The residue was dissolved in EtOAc, washed withH₂O, brine, dried over MgSO₄ and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as anorange oil (5.31 g). LCMS m/z=239.9 [M+H]⁺.

Step B: Preparation of 3-(Methylthio)-5-phenyl-6-p-tolyl-1,2,4-triazine

To a suspension of 2-(hydroxyimino)-2-phenyl-1-p-tolylethanone (1.99 g,8.32 mmol) in a 1:1 mixture of MeOH/H₂O (40.0 mL) was addedhydrazinecarbothioamide (1.134 g, 12.44 mmol) followed by concentratedHCl (0.75 mL, 24.68 mmol). The reaction was stirred at room temperaturefor 1 h then at 60° C. overnight. Additional hydrazinecarbothioamide(˜3×100 mg) was added portionwise and the reaction was stirred at 60° C.until the starting material was consumed. The reaction was neutralizedwith saturated NaHCO₃. The solid was removed by filtration and rinsedwith H₂O. To the solid was added a solution of potassium carbonate (5.78g, 41.8 mmol) in H₂O (85 mL) and the mixture was heated at 90° C.overnight. The reaction mixture was cooled to room temperature thenplaced in an ice bath. Iodomethane (0.52 mL, 8.35 mmol) was added andthe reaction was stirred at 0° C. and then slowly warmed to roomtemperature. After stirring overnight, the solution was decanted. Thesolid was dissolved in CH₂Cl₂, and the solution was washed with H₂O andbrine, dried over MgSO₄, and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as a yellowsolid (1.302 g). LCMS m/z=294.2 [M+H]⁺.

Step C: Preparation of3-(Methylsulfonyl)-5-phenyl-6-p-tolyl-1,2,4-triazine

To a solution of 3-(methylthio)-5-phenyl-6-p-tolyl-1,2,4-triazine (1.302g, 4.44 mmol) in CH₂Cl₂ (25.0 mL) at 0° C. was added MCPBA (2.06 g, 9.19mmol). The reaction mixture was stirred at 0° C. and then warmed to roomtemperature. After 18 h, the reaction was quenched with saturated NaHCO₃solution and extracted with CH₂Cl₂. The combined organic phases werewashed with H₂O and brine, dried over MgSO₄, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as an off-white solid (1.69 g). LCMS m/z=326.2 [M+H]⁺.

Step D: Preparation of 5-Phenyl-6-p-tolyl-1,2,4-triazin-3(2H)-one

To a solution of 3-(methylsulfonyl)-5-phenyl-6-p-tolyl-1,2,4-triazine(98.9 mg, 0.304 mmol) in a 1:1 mixture of H₂O/THF (6.0 mL) was addedpotassium hydroxide (109.1 mg, 1.945 mmol). The mixture was heated atreflux for 1 h. The reaction mixture was cooled to room temperature andneutralized with 1 M HCl, then extracted with CH₂Cl₂. The combinedorganic phases were washed with H₂O and brine, dried over MgSO₄, andconcentrated to give the title compound as a yellow solid (73.7 mg).LCMS m/z=264.1 [M+H]⁺.

Step E: Preparation of2-(((1s,4s)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid and Sodium Salt Thereof

In a reaction vial was placed a mixture of5-phenyl-6-p-tolyl-1,2,4-triazin-3(2H)-one (352.7 mg, 1.340 mmol) andsodium hydride (58.3 mg, 1.458 mmol) in DMF (3.0 mL). The reaction wasstirred at room temperature for 15 min then added a solution oftert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(549.0 mg, 1.331 mmol) in DMF (6.0 mL). The mixture was heated at 45° C.Upon completion of the reaction, the mixture was quenched with H₂O andextracted with EtOAc. The combined organics were washed with brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography. To the above purified material was added 4 MHCl (1.0 mL) in 1,4-dioxane and the mixture was stirred at roomtemperature overnight. Five drops of 10% NaOH solution was added and themixture was extracted with MTBE. The combined organic phases were washedwith brine, dried over MgSO₄, and concentrated. The residue was purifiedby HPLC to give the title compound free acid as a yellowish solid (289.1mg). The free acid was dissolved in acetonitrile, 1 N aqueous sodiumhydroxide (0.646 mL, 0.646 mmol) was added and the mixture waslyophilized to afford the sodium salt of the title compound as anoff-white solid (304.8 mg). LCMS m/z=448.5 [M+H]⁺; ¹H NMR (400 M Hz,DMSO-d₆) δ ppm 1.34-1.54 (m, 7H), 1.67-1.79 (m, 2H), 2.12-2.22 (m, 1H),2.29 (s, 3H), 3.36 (d, J=7.0 Hz, 2H), 3.74 (s, 2H), 4.09 (d, J=7.5 Hz,2H), 7.14 (s, 4H), 7.25-7.34 (m, 4H), 7.36-7.42 (m, 1H).

Example 1.2: Preparation of2-(((1s,4s)-4-((3-Oxo-5,6-di-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 43)

In a reaction vial was placed a mixture of5,6-di-p-tolyl-1,2,4-triazin-3(2H)-one (73.3 mg, 0.264 mmol) and sodiumhydride (13.8 mg, 0.345 mmol) in THF (1.0 mL). The reaction was stirredat room temperature for 30 min then added a solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (101.3 mg,0.246 mmol) in THF (1.5 mL). DMF (1.0 mL) was added to the reactionmixture and it was heated at 50° C. for 45 h. Upon completion, thereaction was quenched with H₂O and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over MgSO₄, andconcentrated. The residue was purified by silica gel columnchromatography to give a yellow oil. To this oil was added 4 M HCl (0.50mL, 2.0 mmol) in 1,4-dioxane and the mixture was stirred at roomtemperature overnight. Upon completion of the reaction, 10% NaOHsolution (6 drops) was added and the reaction mixture was diluted withacetonitrile. The reaction mixture was filtered and purified by HPLC togive the title compound as a yellow solid (35.0 mg). LCMS m/z=462.3[M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 1.36-1.54 (m, 7H), 1.68-1.79(m, 2H), 2.12-2.21 (m, 1H), 2.29-2.32 (m, 6H), 3.39 (d, J=6.9 Hz, 2H),3.98 (s, 2H), 4.08 (d, J=7.5 Hz, 2H), 7.14-7.18 (m, 6H), 7.28-7.31 (m,2H).

Example 1.3: Preparation of2-(((1s,4s)-4-((3-Oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 48)

From 5,6-diphenyl-1,2,4-triazin-3(2H)-one, the title compound wasprepared using a similar method to the one described in Example 1.1,Step E. LCMS m/z=434.4 [M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm1.39-1.54 (m, 7H), 1.69-1.80 (m, 2H), 2.14-2.23 (m, 1H), 3.40 (d, J=6.9Hz, 2H), 3.99 (s, 2H), 4.10 (d, J=7.5 Hz, 2H), 7.24-7.49 (m, 10H).

Example 1.4: Preparation of2-(((1s,4s)-4-((5,6-Bis(4-fluorophenyl)-3-oxo-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 49)

From 5,6-bis(4-fluorophenyl)-1,2,4-triazin-3(2H)-one, the title compoundwas prepared using a similar method to the one described Example 1.1,Step E to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δ ppm1.39-1.55 (m, 7H), 1.69-1.80 (m, 2H), 2.13-2.21 (m, 1H), 3.38 (d, J=6.8Hz, 2H), 3.95 (s, 2H), 4.09 (d, J=7.5 Hz, 2H), 7.17-7.25 (m, 4H),7.29-7.35 (m, 2H), 7.41-7.47 (m, 2H).

Example 1.5: Preparation of2-(((1s,4s)-4-((6-(4-Fluorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 64)

From 1-(4-fluorophenyl)-2-phenylethanone, the title compound wasprepared using a similar method to the one described in Example 1.1 togive a yellow solid. LCMS m/z=452.3 [M+H]⁺. LCMS m/z=452.3 [M+H]⁺; ¹HNMR (400 M Hz, DMSO-d₆) δ ppm 1.38-1.55 (m, 7H), 1.70-1.80 (m, 2H),2.14-2.22 (m, 1H), 3.40 (d, J=6.9 Hz, 2H), 3.99 (s, 2H), 4.10 (d, J=7.5Hz, 2H), 7.15-7.50 (m, 9H).

Example 1.6: Preparation of2-(((1s,4s)-4-((5-(3-Chlorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 67)

From 2-(3-chlorophenyl)-1-phenylethanone, the title compound wasprepared using a similar method to the one described in Example 1.1 togive a yellow solid. LCMS m/z=468.4 [M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δppm 1.38-1.55 (m, 7H), 1.70-1.80 (m, 2H), 2.14-2.22 (m, 1H), 3.40 (d,J=6.9 Hz, 2H), 3.99 (s, 2H), 4.11 (d, J=7.5 Hz, 2H), 7.25-7.54 (m, 9H).

Example 1.7: Preparation of2-(((1s,4s)-4-((6-(4-Methoxyphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 69)

From 1-(4-methoxyphenyl)-2-phenylethanone, the title compound wasprepared using a similar method to the one described in Example 1.1 togive a yellow solid. LCMS m/z=464.5 [M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δppm 1.40-1.54 (m, 7H), 1.68-1.80 (m, 2H), 2.14-2.22 (m, 1H), 3.39 (d,J=6.9 Hz, 2H), 3.75 (s, 3H), 3.99 (s, 2H), 4.09 (d, J=7.5 Hz, 2H),6.86-7.81 (m, 9H).

Example 1.8: Preparation of2-(((1s,4s)-4-((5-(3-Methoxyphenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 70)

From 2-(3-methoxyphenyl)-1-phenylethanone, the title compound wasprepared using a similar method to the one described in Example 1.1 togive a yellow solid. LCMS m/z=464.3 [M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δppm 1.39-1.54 (m, 7H), 1.70-1.80 (m, 2H), 2.15-2.22 (m, 1H), 3.39 (d,J=6.9 Hz, 2H), 3.60 (s, 3H), 3.99 (s, 2H), 4.10 (d, J=7.5 Hz, 2H),6.91-7.03 (m, 3H), 7.22-7.41 (m, 6H).

Example 1.9: Preparation of2-(((1s,4s)-4-((6-(2-Fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 71)

From 1-(2-fluoro-4-methylphenyl)-2-phenylethanone, the title compoundwas prepared using a similar method to the one described in Example 1.1to give a yellow solid. LCMS m/z=466.3 [M+H]⁺; ¹H NMR (400 M Hz,DMSO-d₆) δ ppm 1.36-1.54 (m, 7H), 1.69-1.80 (m, 2H), 2.12-2.21 (m, 1H),2.33 (s, 3H), 3.39 (d, J=6.9 Hz, 2H), 3.98 (s, 2H), 4.10 (d, J=7.5 Hz,2H), 6.94-6.98 (m, 1H), 7.11-7.15 (m, 1H), 7.32-7.49 (m, 6H).

Example 1.10: Preparation of2-(((1s,4s)-4-((6-(4-Chlorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 72)

From 1-(4-chlorophenyl)-2-phenylethanone, the title compound wasprepared using a similar method to the one described in Example 1.1 togive a yellow solid. LCMS m/z=468.5 [M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δppm 1.38-1.54 (m, 7H), 1.70-1.80 (m, 2H), 2.13-2.22 (m, 1H), 3.40 (d,J=6.9 Hz, 2H), 3.99 (s, 2H), 4.10 (d, J=7.5 Hz, 2H), 7.25-7.30 (m, 2H),7.35-7.50 (m, 7H).

Example 1.11: Preparation of2-(((1r,4r)-4-((6-(2-Fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 75)

A reaction vial was charged with6-(2-fluoro-4-methylphenyl)-5-phenyl-1,2,4-triazin-3(2H)-one (fromExample 1.9) (102.9 mg, 0.366 mmol), cesium carbonate (133.8 mg, 0.411mmol) and tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (152.3 mg,0.369 mmol) in DMF (5.0 mL). The reaction mixture was stirred at 60° C.overnight. Upon completion, the reaction was quenched with H₂O andextracted with EtOAc. The combined organic layers were washed withbrine, dried over MgSO₄, and concentrated. The residue was purified bysilica gel column chromatography to give tert-butyl2-(((1r,4r)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetateas a colorless oil (108.5 mg). To this was added 4 M HCl (2.0 mL, 8.0mmol) in 1,4-dioxane at room temperature. The reaction was stirredovernight and concentrated under reduced pressure. The residue wasdissolved in acetonitrile, filtered and purified by HPLC to give thetitle compound as a yellow solid (66.7 mg). LCMS m/z=466.5 [M+H]⁺; ¹HNMR (400 M Hz, DMSO-d₆) δ ppm 0.86-0.99 (m, 2H), 1.01-1.13 (m, 2H),1.45-1.58 (m, 1H), 1.69-1.80 (m, 4H), 1.84-1.96 (m, 1H), 2.33 (s, 3H),3.26 (d, J=6.4 Hz, 2H), 3.95 (s, 2H), 3.99 (d, J=7.1 Hz, 2H), 6.96 (d,J=11.1 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.32-7.49 (m, 6H).

Example 1.12: Preparation of2-(((1r,4r)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 76)

From 5-phenyl-6-p-tolyl-1,2,4-triazin-3(2H)-one, the title compound wasprepared using a similar method to the one described in Example 1.11 togive a yellow solid. LCMS m/z=448.3 [M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δppm 0.86-0.99 (m, 2H), 1.02-1.14 (m, 2H), 1.46-1.58 (m, 1H), 1.70-1.80(m, 4H), 1.85-1.98 (m, 1H), 2.30 (s, 3H), 3.255 (d, J=6.4 Hz, 2H), 3.95(s, 2H), 3.99 (d, J=7.1 Hz, 2H), 7.15 (s, 4H), 7.26-7.49 (m, 5H).

Example 1.13: Preparation of2-(((1s,4s)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 74) Step A: Preparation of2-(3-Fluorophenyl)-2-(hydroxyimino)-1-phenylethanone

From 2-(3-fluorophenyl)-1-phenylethanone, the title compound wasprepared using a similar method to the one described in Example 1.1,Step A to give a yellow solid. LCMS m/z=244.2 [M+H]⁺.

Step B: Preparation of5-(3-Fluorophenyl)-3-(methylthio)-6-phenyl-1,2,4-triazine

From 2-(3-fluorophenyl)-2-(hydroxyimino)-1-phenylethanone, the titlecompound was prepared using a similar method to the one described inExample 1.1, Step B to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δppm 2.72 (s, 3H), 7.45-7.50 (m, 3H), 7.38-7.45 (m, 3H), 7.24-7.36 (m,3H).

Step C: Preparation of5-(3-Fluorophenyl)-3-(methylsulfonyl)-6-phenyl-1,2,4-triazine

From 5-(3-fluorophenyl)-3-(methylthio)-6-phenyl-1,2,4-triazine, thetitle compound was prepared using a similar method to the one describedin Example 1.1, Step C to give a yellow solid. ¹H NMR (400 M Hz,DMSO-d₆) δ ppm 3.61 (s, 3H), 7.55-7.60 (m, 2H), 7.52-7.55 (m, 1H),7.44-7.51 (m, 3H), 7.33-7.43 (m, 3H).

Step D: Preparation of5-(3-Fluorophenyl)-6-phenyl-1,2,4-triazin-3(2H)-one

From 5-(3-fluorophenyl)-3-(methylsulfonyl)-6-phenyl-1,2,4-triazine, thetitle compound was prepared using a similar method to the one describedin Example 1.1, Step D to give a white solid. ¹H NMR (400 M Hz, DMSO-d₆)δ ppm 7.11-7.24 (m, 3H), 7.31-7.43 (m, 4H), 7.25-7.31 (m, 2H), 13.60 (s,1H).

Step E: Preparation of tert-Butyl2-(((1s,4s)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 5-(3-fluorophenyl)-6-phenyl-1,2,4-triazin-3(2H)-one(0.267 g, 1 mmol) in DMF (5 mL) was added Cs₂CO₃ (0.342 g, 1.05 mmol).The reaction was stirred for 15 min. A solution of tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.413 g, 1.000mmol) in DMF (5 mL) was added. The reaction was heated to 60° C. for 18h. The reaction was cooled to room temperature and then diluted withwater and extracted with EtOAc three times. The combined organicextracts were washed with brine, dried (MgSO₄) and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a white solid (0.365 g). ¹H NMR (400 M Hz, CDCl₃) δppm 1.48 (s, 9H), 1.52 (dd, J=6.32, 4.80 Hz, 1H), 1.55-1.66 (m, 6H),1.83-1.93 (m, 2H), 2.35 (bs, 1H), 3.45 (d, J=7.07 Hz, 2H), 3.96 (s, 2H),4.23 (d, J=7.58 Hz, 2H), 7.09-7.17 (m, 1H), 7.19-7.25 (m, 2H), 7.26-7.31(m, 3H), 7.32-7.45 (m, 3H).

Step F: Preparation of2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-fluoro-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate(0.365 g, 0.719 mmol) in dioxane (3.60 mL) was added 4 N HCl (2.88 mL,11.51 mmol). The reaction was stirred overnight and concentrated underreduced pressure to give the title compound (0.299 g) as a yellow oil.LCMS m/z=453.2 [M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 1.34-1.55 (m,6H), 1.69-1.80 (m, 2H), 2.18 (bs, 1H), 3.23-3.28 (m, 1H), 3.40 (d,J=6.82 Hz, 2H), 3.98 (s, 2H), 4.11 (d, J=7.33 Hz, 2H), 7.13-7.22 (m,2H), 7.25-7.32 (m, 3H), 7.32-7.35 (m, 1H), 7.35-7.44 (m, 3H), 12.52 (s,1H).

Example 1.14: Preparation of2-(((1s,4s)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 80) Step A: Preparation of Ethyl3-Oxo-2-m-tolyl-3-p-tolylpropanoate

To a cooled (−78° C.) solution of ethyl 2-m-tolylacetate (1.697 g, 9.52mmol) in THF (10.58 mL) was added LiHMDS (9.52 mL, 9.52 mmol). Thereaction was stirred for 15 minutes and 4-methylbenzoyl chloride (1.546g, 10 mmol) in THF (21.16 mL) was slowly added. The reaction was allowedto warm to room temperature over 2 h. The reaction was quenched withAcOH, diluted with water and extracted with EtOAc three times. Thecombined extracts were washed with brine, dried (MgSO₄) andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a yellow oil (2.213 g). ¹HNMR (400 M Hz, CDCl₃) δ ppm 1.24 (t, J=7.07 Hz, 3H), 2.33 (s, 3H), 2.37(s, 3H), 4.15-4.28 (m, 2H), 5.54 (s, 1H), 7.10 (d, J=7.07 Hz, 1H),7.16-7.25 (m, 5H), 7.85 (d, J=8.08 Hz, 2H).

Step B: Preparation of 2-m-Tolyl-1-p-tolylethanone

To ethyl 3-oxo-2-m-tolyl-3-p-tolylpropanoate (2.213 g, 7.47 mmol) wasadded aqueous HCl solution (8.96 mL, 112 mmol). The reaction was heatedto reflux overnight. The reaction was cooled to room temperature, themixture was diluted with water and extracted with EtOAc three times. Thecombined extracts were washed with brine, dried (MgSO₄) andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a white solid (1.174 g). ¹HNMR (400 M Hz, CDCl₃) δ ppm 2.31-2.32 (m, 3H), 2.40 (s, 3H), 4.21 (s,2H), 7.00-7.09 (m, 3H), 7.20 (t, J=7.45 Hz, 1H), 7.22-7.27 (m, 2H), 7.91(d, J=8.34 Hz, 2H).

Step C: Preparation of 2-(Hydroxyimino)-2-m-tolyl-1-p-tolylethanone

From 2-m-tolyl-1-p-tolylethanone, the title compound was prepared usinga similar method to the one described in Example 1.1, Step A to give ayellow oil. ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 2.32 (s, 3H), 2.39 (s, 3H),7.20-7.26 (m, 1H), 7.26-7.31 (m, 3H), 7.33-7.37 (m, 2H), 7.84 (d, J=8.08Hz, 2H), 12.28 (s, 1H).

Step D: Preparation of 3-(Methylthio)-5-m-tolyl-6-p-tolyl-1,2,4-triazine

From 2-(hydroxyimino)-2-m-tolyl-1-p-tolylethanone, the title compoundwas prepared using a similar method to the one described in Example 1.1,Step B to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 2.27 (s,3H), 2.33 (s, 3H), 2.71 (s, 3H), 7.15-7.23 (m, 4H), 7.23-7.31 (m, 1H),7.33-7.37 (m, 2H), 7.38-7.44 (m, 1H).

Step E: Preparation of3-(Methylsulfonyl)-5-m-tolyl-6-p-tolyl-1,2,4-triazine

From 3-(methylthio)-5-m-tolyl-6-p-tolyl-1,2,4-triazine, the titlecompound was prepared using a similar method to the one described inExample 1.1, Step C to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δppm 2.30 (s, 3H), 2.36 (s, 3H), 3.58 (s, 3H), 7.22-7.31 (m, 4H), 7.34(t, J=7.45 Hz, 1H), 7.47 (d, J=8.08 Hz, 2H), 7.48-7.53 (m, 1H).

Step F: Preparation of 5-m-Tolyl-6-p-tolyl-1,2,4-triazin-3(2H)-one

From 3-(methylsulfonyl)-5-m-tolyl-6-p-tolyl-1,2,4-triazine, the titlecompound was prepared using a similar method to the one described inExample 1.1, Step D to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δppm 2.26 (s, 3H), 2.30 (s, 3H), 7.04 (d, J=7.83 Hz, 1H), 7.14 (s, 3H),7.15-7.22 (m, 2H), 7.25-7.31 (m, 2H), 13.45 (s, 1H).

Step G: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-m-tolyl-6-p-tolyl-1,2,4-triazin-3(2H)-one and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the titlecompound was prepared using a similar method to the one described inExample 1.13, Step E to give a yellow solid. ¹H NMR (400 M Hz, CDCl₃) δppm 1.44-1.52 (m, 2H), 1.48 (s, 9H), 1.52-1.65 (m, 6H), 1.76-1.92 (m,J=3.28 Hz, 2H), 2.30 (s, 3H), 2.36 (s, 3H), 3.45 (d, J=7.07 Hz, 2H),3.95 (s, 2H), 4.21 (d, J=7.58 Hz, 2H), 7.04-7.20 (m, 6H), 7.23 (dd,J=6.82, 2.53 Hz, 1H), 7.47 (s, 1H).

Step H: Preparation of2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-fluoro-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.13, Step F to give a yellow solid. LCMS m/z=462.5[M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 1.31-1.54 (m, 8H), 1.74 (bs,1H), 2.17 (bs, 1H), 2.26 (s, 3H), 2.30 (s, 3H), 3.39 (d, J=6.82 Hz, 2H),3.98 (s, 2H), 4.09 (d, J=7.58 Hz, 2H), 7.06 (d, J=7.58 Hz, 1H),7.13-7.16 (m, 3H), 7.16-7.21 (m, 2H), 7.27 (d, J=7.33 Hz, 1H), 7.29-7.35(m, 1H).

Example 1.15: Preparation of2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 81) Step A: Preparation of tert-Butyl2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

From 6-phenyl-5-m-tolyl-1,2,4-triazin-3(2H)-one and tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the titlecompound was prepared using a similar method to the one described inExample 1.13, Step E to give a yellow oil. ¹H NMR (400 M Hz, DMSO-d₆) δppm 0.86-1.01 (m, 2H), 1.01-1.13 (m, 2H), 1.41 (s, 9H), 1.46-1.59 (m,1H), 1.75 (d, J=10.48 Hz, 4H), 1.87-1.96 (m, J=3.54 Hz, 1H), 2.24 (s,3H), 3.25 (d, J=6.32 Hz, 2H), 3.91 (s, 2H), 3.99 (d, J=7.20 Hz, 2H),7.08 (d, J=7.58 Hz, 1H), 7.19 (t, J=7.96 Hz, 1H), 7.24-7.30 (m, 4H),7.31-7.42 (m, 3H).

Step B: Preparation of2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1r,4r)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.13, Step F to give a yellow solid. LCMS m/z=448.5[M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 0.84-0.99 (m, 2H), 1.01-1.15(m, 2H), 1.45-1.59 (m, J=8.34, 3.28 Hz, 1H), 1.71-1.80 (m, 4H),1.85-2.00 (m, J=8.08, 4.55 Hz, 1H), 2.24 (s, 3H), 3.26 (d, J=6.32 Hz,2H), 3.95 (s, 2H), 3.99 (d, J=7.07 Hz, 2H), 7.09 (d, J=7.83 Hz, 1H),7.16-7.22 (m, 1H), 7.24-7.30 (m, 4H), 7.31-7.43 (m, 3H), 12.48 (bs, 1H).

Example 1.16: Preparation of2-(((1r,4r)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 82) Step A: Preparation of tert-Butyl2-(((1r,4r)-4-((5-(3-Fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-(3-fluorophenyl)-6-phenyl-1,2,4-triazin-3(2H)-one and tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the titlecompound was prepared using a similar method to the one described inExample 1.13, Step E to give an white solid. ¹H NMR (400 M Hz, DMSO-d₆)δ ppm 0.93 (q, J=12.00 Hz, 2H), 1.02-1.14 (m, 2H), 1.41 (s, 9H),1.46-1.59 (m, 1H), 1.76 (d, J=10.99 Hz, 4H), 1.86-1.98 (m, 1H), 3.25 (d,J=6.19 Hz, 2H), 3.91 (s, 2H), 4.00 (d, J=7.07 Hz, 2H), 7.14-7.22 (m,2H), 7.27-7.30 (m, 2H), 7.30-7.35 (m, 1H), 7.34-7.43 (m, 4H).

Step B: Preparation of2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid

From tert-butyl2-(((1r,4r)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.13, Step F to give a yellow solid. LCMS m/z=452.4[M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 0.84-1.00 (m, 2H), 1.02-1.15(m, 2H), 1.41-1.59 (m, 1H), 1.71-1.82 (m, 4H), 1.86-2.00 (m, J=6.32 Hz,1H), 3.26 (d, J=6.32 Hz, 2H), 3.95 (s, 2H), 4.00 (d, J=7.07 Hz, 2H),7.14-7.23 (m, 2H), 7.25-7.31 (m, 3H), 7.32-7.44 (m, 4H), 12.50 (bs, 1H).

Example 1.17: Preparation of2-(((1r,4r)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 83) Step A: Preparation of tert-Butyl2-(((1r,4r)-4-((3-Oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-m-tolyl-6-p-tolyl-1,2,4-triazin-3(2H)-one and tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the titlecompound was prepared using a similar method to the one described inExample 1.13, Step E to give a yellow solid. ¹H NMR (400 M Hz, CDCl₃) δppm 0.93-1.06 (m, 2H), 1.09-1.22 (m, 2H), 1.47 (s, 9H), 1.56-1.69 (m,1H), 1.74-1.92 (m, J=28.04, 10.61 Hz, 4H), 2.03-2.12 (m, 1H), 2.30 (s,3H), 2.36 (s, 3H), 3.32 (d, J=6.32 Hz, 2H), 3.92 (s, 2H), 4.10 (d,J=7.07 Hz, 2H), 7.06-7.12 (m, 1H), 7.11-7.17 (m, 3H), 7.17-7.24 (m, 2H),7.40 (d, J=8.34 Hz, 1H), 7.48 (s, 1H).

Step B: Preparation of2-(((1r,4r)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1r,4r)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.13, Step F to give a yellow solid. LCMS m/z=462.4[M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 0.84-1.00 (m, 2H), 1.01-1.14(m, 2H), 1.46-1.58 (m, 1H), 1.70-1.80 (m, 4H), 1.85-1.98 (m, 1H), 2.26(s, 3H), 2.30 (s, 3H), 3.25 (d, J=6.32 Hz, 2H), 3.95 (s, 2H), 3.98 (d,J=7.07 Hz, 2H), 7.07 (d, J=7.83 Hz, 1H), 7.12-7.18 (m, 4H), 7.18-7.22(m, 1H), 7.24-7.29 (m, 1H), 7.30-7.33 (m, 1H).

Example 1.18: Preparation of2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 84) Step A: Preparation of Ethyl3-Oxo-3-phenyl-2-(thiophen-2-yl)propanoate

From benzoyl chloride and ethyl 2-(thiophene-2-yl)acetate, the titlecompound was prepared using a similar method to the one described inExample 1.14, Step A to give a clear oil. ¹H NMR (400 M Hz, CDCl₃) δ ppm1.22 (t, J=7.07 Hz, 3H), 4.16-4.26 (m, 2H), 5.88 (s, 1H), 6.96-7.02 (m,1H), 7.07 (d, J=3.03 Hz, 1H), 7.31 (dd, J=5.18, 1.14 Hz, 1H), 7.46 (t,J=7.71 Hz, 2H), 7.57 (t, J=7.33 Hz, 1H), 7.98-8.02 (m, 2H).

Step B: Preparation of 1-Phenyl-2-(thiophen-2-yl)ethanone

From ethyl 3-oxo-3-phenyl-2-(thiophen-2-yl)propanoate, the titlecompound was prepared using a similar method to the one described inExample 1.14, Step B to give a yellow solid. ¹H NMR (400 M Hz, CDCl₃) δppm 4.48 (s, 2H), 6.91-6.95 (m, 1H), 6.95-6.99 (m, 1H), 7.22 (d, J=5.05Hz, 1H), 7.47 (t, J=7.71 Hz, 2H), 7.52-7.60 (m, 1H), 8.02 (d, J=8.34 Hz,2H).

Step C: Preparation of2-(Hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone

From 1-phenyl-2-(thiophen-2-yl)ethanone, the title compound was preparedusing a similar method to the one described in Example 1.1, Step A togive a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 7.17 (dd, J=5.18,3.92 Hz, 1H), 7.51-7.58 (m, 3H), 7.64-7.71 (m, 1H), 7.86 (dd, J=5.18,1.14 Hz, 1H), 7.88-7.92 (m, 2H), 13.00 (s, 1H).

Step D: Preparation of2-(Hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone

From 2-(hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone, the titlecompound was prepared using a similar method to the one described inExample 1.1, Step B to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δppm 2.70 (s, 3H), 6.91 (dd, J=3.92, 1.14 Hz, 1H), 7.04 (dd, J=5.05, 3.79Hz, 1H), 7.52-7.64 (m, 5H), 7.90 (dd, J=4.93, 1.14 Hz, 1H).

Step E: Preparation of3-(Methylsulfonyl)-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazine

From 2-(hydroxyimino)-1-phenyl-2-(thiophen-2-yl)ethanone, the titlecompound was prepared using a similar method to the one described inExample 1.1, Step C to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δppm 3.58 (s, 3H), 7.07-7.15 (m, 2H), 7.56-7.77 (m, 5H), 8.02 (dd,J=4.74, 1.33 Hz, 1H).

Step F: Preparation of6-Phenyl-5-(thiophen-2-yl)-1,2,4-triazin-3(2H)-one

From 3-(methylsulfonyl)-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazine, thetitle compound was prepared using a similar method to the one describedin Example 1.1, Step D to give a yellow solid. ¹H NMR (400 M Hz,DMSO-d₆) δ ppm 6.67 (dd, J=4.04, 1.01 Hz, 1H), 7.00 (dd, J=5.05, 4.04Hz, 1H), 7.47-7.59 (m, 5H), 7.91 (dd, J=5.05, 1.01 Hz, 1H), 13.32 (s,1H).

Step G: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

From 6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-3(2H)-one and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, the titlecompound was prepared using a similar method to the one described inExample 1.13, Step E to give a yellow solid. ¹H NMR (400 M Hz, CDCl₃) δppm 1.41-1.46 (m, 4H), 1.48 (s, 9H), 1.49-1.54 (m, 2H), 1.56-1.62 (m,2H), 1.81-1.93 (m, J=6.57, 3.79 Hz, 1H), 2.25-2.33 (m, J=6.44, 3.41 Hz,1H), 3.43 (d, J=6.82 Hz, 2H), 3.94 (s, 2H), 4.17 (d, J=7.58 Hz, 2H),6.87-6.90 (m, 1H), 6.91-6.94 (m, 1H), 7.41-7.49 (m, 4H), 7.50-7.54 (m,1H), 7.56 (dd, J=5.05, 1.01 Hz, 1H).

Step H: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.13, Step F to give a yellow solid. LCMS m/z=440.5[M+H]⁺; ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 1.33-1.52 (m, 8H), 1.67-1.78(m, J=10.11, 10.11 Hz, 1H), 2.07-2.18 (m, J=3.03 Hz, 1H), 3.37 (d,J=7.07 Hz, 2H), 3.97 (s, 2H), 4.04 (d, J=7.58 Hz, 2H), 6.69 (dd, J=3.79,1.01 Hz, 1H), 7.00 (dd, J=5.05, 3.79 Hz, 1H), 7.50-7.60 (m, 5H), 7.91(dd, J=5.05, 1.01 Hz, 1H).

Example 1.19: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 31) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 5-bromo-6-phenylpyridazin-3(2H)-one (1.522 g, 6.06mmol) in DMF (90 mL) was added tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (2.50 g, 6.06mmol), potassium 2-methylpropan-2-olate (1.360 g, 12.12 mmol) and18-crown-6 (0.320 g, 1.212 mmol). The reaction was stirred at 40° C. for16 h, quenched with water (40 mL), extracted with EtOAc (4×50 mL), andwashed with brine. The combined organic phases were dried over MgSO₄,filtered, and concentrated to give a brown oil. The brown oil waspurified by silica gel column chromatography to give the title compoundas a yellow oil (1.346 g). LCMS m/z=491.3 [M+H]⁺; ¹H NMR (400 M Hz,CDCl₃) δ ppm, 1.37-1.64 (m, 17H), 1.80-1.90 (m, 1H), 2.23 (bs, 1H), 3.42(d, J=7.07 Hz, 2H), 3.94 (s, 2H), 4.17 (d, J=7.71 Hz, 2H), 7.44-7.49 (m,4H), 7.50-7.55 (m, 2H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

A vial was charged with 3-chloro-2-fluorophenylboronic acid (10.64 mg,0.061 mmol), tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate (30.0 mg, 0.061 mmol), aqueousNa₂CO₄ (2 M, 0.061 mL, 0.122 mmol), and Pd(PPh₃)₄(2.12 mg, 0.002 mmol)in a mixture of EtOH (1 mL) and benzene (3 mL). The reaction was heatedunder microwave irradiation at 130° C. for 1 h. The reaction mixture wasdiluted with water and the organic phase was removed. The aqueous layerwas extracted with EtOAc three times. The combined organic phases weredried over MgSO₄, filtered and concentrated to give a white solid. Thiswhite solid was purified by silica gel column chromatography to give thetitle compound as a clear oil (0.033 g). LCMS m/z=541.3 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

To a solution of tert-butyl2-(((1s,4s)-4-((4-(3-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate(0.033 g, 0.061 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (0.152mL, 0.610 mmol). The reaction was stirred at 25° C. for 16 h andconcentrated to give a yellow oil. The yellow oil was purified by HPLCto give the title compound as a clear oil (0.012 g). LCMS m/z=485.5[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.43-1.65 (m, 8H), 1.78-1.94 (m,1H), 2.34 (bs, 1H), 3.52 (d, J=7.07 Hz, 2H), 4.11 (s, 2H), 4.28 (d,J=7.71 Hz, 2H), 7.03-7.12 (m, 3H), 7.14-7.19 (m, 2H), 7.23-7.29 (m, 2H),7.29-7.35 (m, 1H), 7.37-7.45 (m, 1H).

Example 1.20: Preparation of2-(((1s,4s)-4-((4-(5-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 45) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(5-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-methylthiophen-2-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=509.5[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(5-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(5-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=453.3[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.39-1.62 (m, 8H), 1.73-1.91 (m,1H), 2.28 (bs, 1H), 2.43 (s, 3H), 3.50 (d, J=6.95 Hz, 2H), 4.11 (s, 2H),4.22 (d, J=7.71 Hz, 2H), 6.54-6.59 (m, 2H), 7.16-7.21 (m, 1H), 7.29-7.48(m, 5H).

Example 1.21: Preparation of2-(((1s,4s)-4-((4-(4-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 50) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((4-(4-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 4-methylthiophen-2-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=509.4[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(4-Methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(4-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=453.2[M+H]⁺.

Example 1.22: Preparation of2-(((1s,4s)-4-((4-(2-Methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 51) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((4-(2-Methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 2-methylpyridin-4-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=504.4[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(2-Methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(2-methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=448.4[M+H]⁺.

Example 1.23: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 8) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 2,3-difluorophenylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=525.7[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(2,3-Difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(2,3-difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=469.5[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.42-1.67 (m, 8H), 1.77-1.93 (m,1H), 2.34 (bs, 1H), 3.52 (d, J=6.95 Hz, 2H), 4.13 (s, 2H), 4.31 (d,J=7.58 Hz, 2H), 6.92-7.01 (m, 1H), 7.07-7.14 (m, 1H), 7.14-7.30 (m, 6H),7.30-7.37 (m, 1H).

Example 1.24: Preparation of2-(((1s,4s)-4-((4-(2-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 54) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((4-(2-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 2-fluoropyridin-3-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=508.3[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(2-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(2-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=452.3[M+H]⁺

Example 1.25: Preparation of2-(((1s,4s)-4-((4-(6-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 55) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(6-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 6-fluoropyridin-3-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=508.2[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(6-Fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(6-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=452.3[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.42-1.67 (m, 8H), 1.77-1.93 (m,1H), 2.33 (bs, 1H), 3.52 (d, J=6.95 Hz, 2H), 4.13 (s, 2H), 4.30 (d,J=7.58 Hz, 2H), 6.88 (dd, J=8.46, 2.78 Hz, 1H), 7.12-7.23 (m, 3H),7.28-7.41 (m, 3H), 7.46-7.54 (m, 1H), 8.08 (d, J=2.40 Hz, 1H).

Example 1.26: Preparation of2-(((1s,4s)-4-((4-(2-Chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 56) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((4-(2-Chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 2-chloropyridin-4-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMSm/z=524.7, 526.6 [M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(2-Chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(2-chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMSm/z=468.4, 470.5 [M+H]⁺.

Example 1.27: Preparation of2-(((1s,4s)-4-((4-(2-Fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 59) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((4-(2-Fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 2-fluoropyridin-4-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=508.4[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(2-Fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(2-fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=452.3[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.42-1.65 (m, 8H), 1.76-1.94 (m,1H), 2.32 (bs, 1H), 3.51 (d, J=6.95 Hz, 2H), 4.11 (s, 2H), 4.26 (d,J=7.58 Hz, 2H), 6.73 (s, 1H), 6.89-6.93 (m, 1H), 7.04 (s, 1H), 7.13-7.18(m, 2H), 7.25-7.40 (m, 3H), 8.16 (d, J=5.05 Hz, 1H).

Example 1.28: Preparation of2-(((1s,4s)-4-((4-(5-Methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 60) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((4-(5-Methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-methylpyridin-3-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=504.5[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(5-Methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(5-methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=448.3[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.42-1.65 (m, 8H), 1.78-1.94 (m,1H), 2.29 (bs, 1H), 2.44 (bs, 3H), 3.51 (d, J=7.07 Hz, 2H), 4.10 (s,2H), 4.30 (d, J=7.07 Hz, 2H), 7.10-7.17 (m, 3H), 7.29-7.42 (m, 3H), 7.73(s, 1H), 8.43 (s, 1H), 8.60 (s, 1H).

Example 1.29: Preparation of2-(((1s,4s)-4-((4-(5-Chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 66) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((4-(5-Chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-chloropyridin-3-ylboronic acid and tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step B, to give a white solid. LCMS m/z=524.7[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((4-(5-Chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((4-(5-chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.19, Step C, to give a white solid. LCMS m/z=468.4[M+H]⁺.

Example 1.30: Preparation of2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 73) Step A: Preparation of2-(Hydroxyimino)-1-phenyl-2-m-tolylethanone

From 1-phenyl-2-m-tolylethanone, the title compound was prepared using asimilar method to the one described in Example 1.1, Step A to give ayellow oil. ¹H NMR (400 M Hz, CDCl₃) δ ppm 2.28-2.40 (m, 3H), 3.49 (d,J=5.05 Hz, 1H), 7.19-7.27 (m, 1H), 7.30-7.36 (m, 1H), 7.37-7.42 (m, 1H),7.44-7.53 (m, 2H), 7.55-7.65 (m, 1H), 7.94-7.99 (m, 1H), 8.00-8.03 (m,1H), 8.06 (s, 1H).

Step B: Preparation of 3-(Methylthio)-6-phenyl-5-m-tolyl-1,2,4-triazine

From 2-(hydroxyimino)-1-phenyl-2-m-tolylethanone, the title compound wasprepared using a similar method to the one described in Example 1.1,Step B to give a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δ ppm 2.25 (s,3H), 2.72 (s, 3H), 7.15-7.31 (m, 3H), 7.35-7.52 (m, 6H).

Step C: Preparation of3-(Methylsulfonyl)-6-phenyl-5-m-tolyl-1,2,4-triazine

From 3-(methylthio)-6-phenyl-5-m-tolyl-1,2,4-triazine, the titlecompound was prepared using a similar method to the one described inExample 1.1, Step C as a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δ ppm2.28 (s, 3H), 3.60 (s, 3H), 7.24-7.28 (m, 2H), 7.32-7.38 (m, 1H),7.44-7.49 (m, 2H), 7.50-7.61 (m, 3H), 7.86-7.91 (m, 1H).

Step D: Preparation of 6-Phenyl-5-m-tolyl-1,2,4-triazin-3(2H)-one

From 3-(methylsulfonyl)-6-phenyl-5-m-tolyl-1,2,4-triazine, the titlecompound was prepared using a similar method to the one described inExample 1.1, Step D as a yellow solid. ¹H NMR (400 M Hz, DMSO-d₆) δ ppm2.24 (s, 3H), 7.06 (d, J=7.83 Hz, 1H), 7.18 (t, J=7.83 Hz, 1H),7.23-7.30 (m, 4H), 7.30-7.41 (m, 3H), 13.52 (s, 1H).

Step E: Preparation of2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl 2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetateand 6-phenyl-5-m-tolyl-1,2,4-triazin-3(2H)-one, the title compound wasprepared using a similar method to the one described in Example 1.1,Step E to give a yellow oil. LCMS m/z=448.5 [M+H]⁺; ¹H NMR (400 M Hz,DMSO-d₆) δ ppm 1.37-1.53 (m, 6H), 1.68-1.80 (m, 2H), 2.13-2.21 (m,J=3.79 Hz, 1H), 2.24 (s, 3H), 3.23-3.27 (m, 1H), 3.40 (d, J=7.07 Hz,2H), 3.99 (s, 2H), 4.10 (d, J=7.58 Hz, 2H), 7.08 (d, J=7.58 Hz, 1H),7.19 (t, J=7.83 Hz, 1H), 7.23-7.30 (m, 4H), 7.31-7.41 (m, 3H), 12.50 (s,1H).

Example 1.31: Preparation of t-Butyl2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate Step A:Preparation of (1s,4s)-Diethyl Cyclohexane-1,4-dicarboxylate

To a solution of (1s,4s)-cyclohexane-1,4-dicarboxylic acid (25 g, 145mmol) in ethanol (150 mL) was added concentrated H₂SO₄ (1 mL). Thereaction was refluxed for 16 h, cooled to room temperature andconcentrated. The residue was extracted with EtOAc and saturated NaHCO₃,washed with brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated to provide the title compound as a colorless oil (30.5 g).¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (t, J=7.14 Hz, 6H), 1.64-1.70 (m,4H), 1.87-1.92 (m, 4H), 2.44-2.46 (m, 2H), 4.11-1.46 (quartet, J=7.12Hz, 4H).

Step B: Preparation of (1s,4s)-Cyclohexane-1,4-diyldimethanol

To a solution of (1s,4s)-diethyl cyclohexane-1,4-dicarboxylate (13.0 g,56.9 mmol) in THF (500 mL) was added lithium aluminum hydride (4.54 g,120 mmol) in portions at 0° C. The mixture was stirred at thattemperature for 2 h and quenched with cold water, filtered andconcentrated to give the title compound as a colorless oil (8.2 g). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.42 (m, 8H), 1.46-1.54 (m, 2H),3.26-3.31 (m, 4H), 4.27-4.30 (t, J=5.31 Hz, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methoxy)acetate

To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol (18.2 g, 126mmol) in toluene (200 mL) was added NaOH (50% aqueous, 60 mL) andtetrabutylammonium iodide (2.331 g, 6.31 mmol), followed bytert-butyl-2-bromoacetate (20.50 mL, 139 mmol) at room temperature. Thereaction mixture was stirred vigorously at room temperature for 2 h anddiluted with ethyl acetate and water. After separation, the aqueouslayer was extracted with EtOAc (3×30 mL). The combined organic layerswere dried over MgSO₄, concentrated, and purified by silica gel columnchromatography to give the title compound as a colorless oil (13.5 g).¹H NMR (400 MHz, CDCl₃) δ ppm 1.35-1.47 (m, 4H), 1.48 (s, 9H), 1.50-1.60(m, 4H), 1.63-1.74 (m, 1H), 1.79-1.92 (m, 1H), 3.42 (d, J=6.95 Hz, 2H),3.55 (d, J=6.82 Hz, 2H), 3.93 (s, 1H), 3.94 (s, 2H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate

To a solution of tert-butyl2-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (12.0 g, 46.4mmol) in dichloromethane (150 mL) were added triethylamine (4.70 g, 46.4mmol) and 4-(dimethylamino)pyridine (0.567 g, 4.64 mmol), followed by4-methylbenzene-1-sulfonyl chloride (8.86 g, 46.4 mmol). The reactionwas stirred at room temperature for 16 h. The solvent was removed andthe residue was extracted with EtOAc/H₂O. The organic extracts weredried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale liquid(9.5 g). LCMS m/z=413.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28-1.43(m, 4H), 1.46-1.48 (m, 9H), 1.49-1.56 (m, 4H), 1.76-1.91 (m, 2H), 2.45(s, 3H), 3.36 (d, J=6.95 Hz, 2H), 3.92 (d, J=7.05 Hz, 2H), 3.92 (s, 2H),7.35 (d, J=8.46 Hz, 2H), 7.78 (d, J=8.34 Hz, 2H).

Example 1.32: Preparation of tert-Butyl2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate Step A:Preparation of (1s,4s)-Cyclohexane-1,4-diyldimethanol

To a solution of (1s,4s)-cyclohexane-1,4-dicarboxylic acid (8.617 g,50.0 mmol) in THF (50.0 mL) at 0° C. was added LAH (100 mL, 200 mmol)via cannula. The reaction mixture was stirred at 0° C. and allowed towarm to room temperature overnight. After 24 h, the reaction wasquenched with H₂O (7.6 mL), 10% NaOH (15.2 mL), and followed byadditional H₂O (22.8 mL). The precipitate formed was filtered and rinsedwith EtOAc. The filtrate was washed with brine, dried over MgSO4, andconcentrated to give the title compound as a colorless oil (5.91 g).

Step B: Preparation of ((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methyl4-methylbenzenesulfonate

To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol (5.91 g, 41.0mmol) in CH₂Cl₂ (300 mL) was added 4-methylbenzene-1-sulfonyl chloride(7.80 g, 40.9 mmol) and triethylamine (7.75 mL, 55.6 mmol) followed byDMAP (0.246 g, 2.014 mmol). The resulting reaction mixture was stirredat room temperature overnight. Upon completion, the solvent was removedunder reduced pressure and the residue was washed with H₂O and brine,dried over MgSO₄ and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a colorless oil(5.30 g). LCMS m/z=299.4.

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-(Tosyloxymethyl)cyclohexyl)methoxy)acetate

To a solution of ((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl4-methylbenzenesulfonate (5.30 g, 17.76 mmol) in CH₂Cl₂ (100 mL) wasadded diacetoxyrhodium (472.4 mg, 1.069 mmol). The resulting reactionmixture was stirred at room temperature for 30 min then placed in an icebath. To the reaction mixture at 0° C. was added dropwise a solution oftert-butyl 2-diazoacetate (4.0 g, 28.1 mmol) in CH₂Cl₂ (10.0 mL) over 1h. The reaction mixture was stirred at 0° C. and slowly warmed to roomtemperature. After 48 h, the reaction mixture was filtered throughCelite® which was rinsed with CH₂Cl₂ and the combined filtrate andrinsings were concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a colorless oil(5.659 g).

Example 1.33: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 61) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((3-Chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 6-chloro-5-phenylpyridazin-3(2H)-one (0.480 g, 2.323mmol), in DMF (34 mL) was added tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.958 g, 2.323mmol), potassium 2-methylpropan-2-olate (0.521 g, 4.650 mmol) and18-crown-6 (0.123 g, 0.465 mmol). The resulting mixture was stirred at40° C. for 16 h. The reaction mixture was quenched with water (20 mL),extracted with EtOAc (4×20 mL) and washed with brine. The combinedorganics were dried over MgSO₄, filtered, and concentrated to give abrown oil. This brown oil was purified by silica gel columnchromatography to give the title compound as a yellow oil (1.346 g).LCMS m/z=447.5 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.38-1.66 (m, 17H),1.82-1.93 (m, 1H), 2.24 (bs, 1H), 3.45 (d, J=7.07 Hz, 2H), 3.96 (s, 2H),4.13 (d, J=7.71 Hz, 2H), 6.89 (s, 1H), 7.40-7.53 (m, 5H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

A vial was charged with thiophen-3-ylboronic acid (31.0 mg, 0.246 mmol),tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate(100 mg, 0.224 mmol), aqueous Na₂CO₃ (2 M solution, 0.224 mL, 0.447mmol), and Pd(PPh₃)₄ (7.76 mg, 0.007 mmol) in a mixture of EtOH (1 mL)and benzene (3 mL). The reaction was heated in the under microwaveirradiation at 130° C. for 1 h. The reaction mixture was diluted withwater and the organic layer was removed. The aqueous layer was extractedthree times with EtOAc. The combined organics were dried over MgSO₄,filtered and concentrated. The residue was purified by HPLC to give thetitle compound as a clear oil (0.037 g). LCMS m/z=495.4 [M+H]⁺.

Step C: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate(0.037 g, 0.074 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (0.186mL, 0.744 mmol). The reaction mixture was stirred at 25° C. for 16H andevaporated down to give a yellow oil. This yellow oil was purified byHPLC to give the title compound as a white solid (0.025 g). LCMSm/z=439.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42-1.67 (m, 8H),1.76-1.93 (m, 1H), 2.32 (bs, 1H), 3.52 (d, J=6.95 Hz, 2H), 4.12 (s, 2H),4.25 (d, J=7.58 Hz, 2H), 6.91-7.01 (m, 3H), 7.14-7.23 (m, 3H), 7.31-7.46(m, 3H).

Example 1.34: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 57) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From pyridin-4-ylboronic acid and tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step B, to give a white solid. LCMS m/z=490.5[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step C, to give a white solid. LCMS m/z=434.4[M+H]⁺.

Example 1.35: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 42) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From pyridin-3-ylboronic acid and tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step B, to give a white solid. LCMS m/z=490.5[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step C, to give a white solid. LCMS m/z=434.3[M+H]⁺.

Example 1.36: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 58) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From thiophen-2-ylboronic acid and tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step B, to give a white solid. LCMS m/z=495.5[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step B, to give a white solid. LCMS m/z=439.3[M+H]⁺.

Example 1.37: Preparation of2-(((1s,4s)-4-((3-(5-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 62) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((3-(5-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-methylpyridin-3-ylboronic acid and tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step B, to give a white solid. LCMS m/z=504.4[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((3-(5-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((3-(5-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step C, to give a white solid. LCMS m/z=448.5[M+H]⁺.

Example 1.38: Preparation of2-(((1s,4s)-4-((3-(6-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 63) Step A:Preparation of tert-Butyl2-(((1s,4s)-4-((3-(6-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 6-methylpyridin-3-ylboronic acid hydrate and tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step B, to give a white solid. LCMS m/z=504.4[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((3-(6-Methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid

From tert-butyl2-(((1s,4s)-4-((3-(6-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step C, to give a white solid. LCMS m/z=448.5[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.40-1.70 (m, 8H), 1.80-1.93 (m,1H), 2.32 (bs, 1H), 2.82 (s, 3H), 3.51 (d, J=6.95 Hz, 2H), 4.10 (s, 2H),4.29 (d, J=7.71 Hz, 2H), 7.07 (s, 1H), 7.16 (d, 2H), 7.35 (d, J=8.46 Hz,1H), 7.37-7.50 (m, 3H), 7.63 (dd, J=8.40, 1.71 Hz, 1H), 8.94 (s, 1H).

Example 1.39: Preparation of2-(((1s,4s)-4-((3-(6-Chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 65) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((3-(6-Chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

From 6-chloropyridin-3-ylboronic acid and tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step B, to give a white solid. LCMS m/z=524.7[M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((3-(6-Chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

From tert-butyl2-(((1s,4s)-4-((3-(6-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.33, Step C, to give a white solid. LCMS m/z=468.5[M+H]⁺.

Example 1.40: Preparation of2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 77) Step A: Preparation of Ethyl3-Oxo-3-phenyl-2-(pyridin-3-yl)propanoate

To a cooled solution (−78° C.) of ethyl 2-(pyridin-3-yl)acetate (1.842mL, 12.11 mmol) in THF (12.2 mL) was added LiHMDS (12.11 mL, 12.11 mmol)and the mixture was stirred 15 min. A solution of benzoyl chloride(1.474 mL, 12.71 mmol) in THF (24.4 mL) was added slowly and the mixturewas warmed to room temperature and stirred for 12 h. The reaction wasquenched with AcOH (1.386 mL, 24.21 mmol), diluted with H₂O (50 mL), andextracted with EtOAc (3×75 mL). The combined extracts were washed withbrine, dried over MgSO₄ and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as a clearoil (1.82 g). LCMS m/z=270.2 [M+H]⁺.

Step B: Preparation of 1-Phenyl-2-(pyridine-3-yl)ethanone

Ethyl 3-oxo-3-phenyl-2-(pyridin-3-yl)propanoate (1.82 g, 6.76 mmol) wasdissolved in hydrogen chloride (8.11 mL, 101.0 mmol) and heated to 100°C. overnight. The reaction was then diluted with H₂O (25 mL), extractedwith EtOAc (3×50 mL), dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a clear oil (0.894 g). LCMS m/z=198.3 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 4.29 (s, 2H), 7.27 (dd, J=7.07, 5.56 Hz, 1H),7.49 (t, J=7.58 Hz, 2H), 7.55-7.64 (m, 2H), 7.99-8.05 (m, 2H), 8.49-8.56(m, 2H).

Step C: Preparation of2-(Hydroxyimino)-1-phenyl-2-(pyridin-3-yl)ethanone

To a solution of 1-phenyl-2-(pyridine-3-yl)ethanone (0.494 g, 2.505mmol) in EtOH (36.8 mL) at room temperature was added tert-butyl nitrite(0.586 mL, 4.93 mmol) dropwise followed by sodium ethoxide (0.435 g,2.55 mmol). The reaction was stirred at room temperature overnight. Uponcompletion, the solvent was evaporated to give a yellow oil. This oilwas then diluted with H₂O (25 mL), extracted with EtOAc (3×50 mL), driedover MgSO₄, filtered and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as a yellowsolid (0.214 g). LCMS m/z=227.4 [M+H]⁺.

Step D: Preparation of3-(Methylthio)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine

To a suspension of 2-(hydroxyimino)-1-phenyl-2-(pyridin-3-yl)ethanone(0.434 g, 1.918 mmol) in a 1:1 mixture of EtOH/H₂O (8.0 mL) was addedhydrazinecarbothioamide (0.262 g, 2.88 mmol) followed by concentratedHCl (0.307 mL, 3.84 mmol). The reaction was stirred at room temperaturefor 1 h then heated to 90° C. overnight. Upon completion, the reactionmixture was neutralized with saturated NaHCO₃. The solid formed wasfiltered and rinsed with H₂O. The solid was added to a solution ofpotassium carbonate (1.326 g, 9.59 mmol) in H₂O (50 mL) and heated to90° C. overnight. Upon completion, the reaction mixture was cooled toroom temperature then placed in an ice bath. To the ice cooled mixturewas added iodomethane (0.119 mL, 1.918 mmol). The reaction was stirredat 0° C. and slowly warmed to room temperature. After stirringovernight, the solution was extracted with CH₂Cl₂ (3×75 mL), washed withH₂O, brine, dried over MgSO₄ and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound as ayellow solid (0.152 g). LCMS m/z=281.1 [M+H]⁺.

Step E: Preparation of3-(Methylsulfonyl)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine

To a solution of 3-(methylthio)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine(0.152 g, 0.542 mmol) in CH₂Cl₂ (3.0 mL) at 0° C. was added MCPBA (0.255g, 1.139 mmol). The reaction mixture was stirred at 0° C. and thenallowed to warm to room temperature overnight. The reaction was quenchedwith saturated NaHCO₃ solution and extracted with CH₂Cl₂. The organicextracts were washed with H₂O, brine, dried over MgSO₄ and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a yellow solid (0.169 g). LCMS m/z=313.3 [M+H]⁺.

Step F: Preparation of6-Phenyl-5-(pyridine-3-yl)-1,2,4-triazin-3(2H)-one

To a solution of3-(methylsulfonyl)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine (0.035 g,0.112 mmol) in a 1:1 mixture of H₂O/THF (1.5 mL) was added potassiumhydroxide (0.037 g, 0.560 mmol). The reaction was heated at reflux for 2h. Upon completion, the reaction mixture was cooled to room temperatureand neutralized with 1 M HCl, then extracted with EtOAc. The combinedorganic layers were washed with H₂O, brine, dried over MgSO₄ andconcentrated to give the title compound as a yellow solid (0.026 g)without further purification. LCMS m/z=251.1 [M+H]⁺.

Step G: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

To a solution 6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-3(2H)-one (0.034g, 0.136 mmol) in dry DMF (1.5 mL) was added cesium carbonate (0.044 g,0.136 mmol) and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (0.056 g, 0.136mmol). The reaction mixture was heated to 80° C. and stirred for 1 h.Upon completion, the reaction mixture was quenched with H₂O andextracted with EtOAc (twice). The combined organics layers were washedwith brine, dried over MgSO₄, filtered and concentrated down to give thetitle compound as a yellow solid (0.067 g) without further purification.LCMS m/z=491.4 [M+H]⁺.

Step H: Preparation of2-(((1s,4s)-4-((3-Oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

To tert-butyl2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetateobtained above was added 4 M HCl (0.512 mL, 2.049 mmol) in 1,4-dioxane.The reaction was stirred at 25° C. for 16 h. The reaction was evaporateddown to give a yellow oil. This yellow oil was purified by HPLC to givethe TFA salt of the title compound (0.042 g) as a white solid. LCMSm/z=435.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.43-1.68 (m, 8H),1.83-1.96 (m, 1H), 2.32 (bs, 1H), 3.52 (d, J=7.07 Hz, 2H), 4.11 (s, 2H),4.30 (d, J=7.07 Hz, 2H), 7.28 (s, 2H), 7.41 (t, J=7.45 Hz, 2H), 7.46 (d,J=7.33 Hz, 1H), 7.63 (d, 1H), 8.26 (d, J=8.08 Hz, 1H), 8.79 (s, 2H).

Example 1.41: Preparation of2-(((1s,4s)-4-((3-Oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 78) Step A: Preparation of2-(Hydroxyimino)-1-(pyridin-3-yl)-2-p-tolylethanone

From 1-(pyridin-3-yl)-2-p-tolylethanone, the title compound was preparedusing a similar method to the one described in Example 1.40, Step C, togive a yellow oil. LCMS m/z=241.1 [M+H]⁺.

Step B: Preparation of3-(Methylthio)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine

From 2-(hydroxyimino)-1-(pyridin-3-yl)-2-p-tolylethanone, the titlecompound was prepared using a similar method to the one described inExample 1.40, Step D, to give a yellow solid. LCMS m/z=295.2 [M+H]⁺.

Step C: Preparation of3-(Methylsulfonyl)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine

From 3-(methylthio)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine, the titlecompound was prepared using a similar method to the one described inExample 1.40, Step E, to give a yellow solid. LCMS m/z=327.2 [M+H]⁺.

Step D: Preparation of6-(Pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-3(2H)-one

From 3-(methylsulfonyl)-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazine, thetitle compound was prepared using a similar method to the one describedin Example 1.40, Step F, to give a yellow solid. LCMS m/z=265.1 [M+H]⁺.

Step E: Preparation of tert-Butyl2-(((1s,4s)-4-((3-oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

From 6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-3(2H)-one, the titlecompound was prepared using a similar method to the one described inExample 1.40, Step G, to give a yellow solid. LCMS m/z=505.4 [M+H]⁺.

Step F: Preparation of2-(((1s,4s)-4-((3-Oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate,the TFA salt of the title compound was prepared using a similar methodto the one described in Example 1.40, Step H, to give a white solid.LCMS m/z=449.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.43-1.75 (m, 8H),1.82-1.94 (m, 2H), 2.41 (s, 3H), 3.54 (d, J=7.07 Hz, 2H), 4.14 (s, 2H),4.32 (d, J=8.34 Hz, 2H), 7.17-7.24 (m, 2H), 7.39 (d, J=8.08 Hz, 2H),7.66 (bs, 1H), 7.85 (d, J=8.08 Hz, 1H), 9.20 (bs, 1H), 9.45 (bs, 1H).

Example 1.42: Preparation of2-(((1s,4s)-4-((3-Oxo-5-(pyridin-4-yl)-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 79)

From 2-(pyridin-4-yl)-1-p-tolylethanone, the TFA salt of the titlecompound was prepared using a similar method to the one described inExample 1.41 to give a white solid. LCMS m/z=449.3 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.43-1.69 (m, 8H), 1.78-1.94 (m, 2H), 2.40 (s, 3H),3.52 (d, J=7.07 Hz, 2H), 4.11 (s, 2H), 4.26 (d, J=7.58 Hz, 2H), 7.12 (d,J=8.00 Hz, 2H), 7.20 (d, J=8.00 Hz, 2H), 7.69 (bs, 2H), 8.75 (bs, 2H).

Example 1.43: Preparation of2-(((1r,4r)-4-((4-(3-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 1)

A mixture of tert-butyl2-(((1r,4r)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate(30.0 mg, 0.089 mmol), 5-(3-methoxyphenyl)-6-phenylpyridazin-3(2H)-one(27.3 mg, 0.098 mmol), potassium tert-butoxide (25.01 mg, 0.223 mmol)and 18-crown-6 (4.71 mg, 0.018 mmol) in DMF (2 mL) was stirred overnightat room temperature. The reaction was quenched with water, extractedwith EtOAc and dried over anhydrous MgSO₄ and concentrated. The residuewas purified by preparative HPLC to give the title compound as a paleyellow solid (4.90 mg). LCMS m/z=463.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 0.96-1.06 (m, 2H), 1.13-1.23 (m, 2H), 1.63-1.69 (m, 1H), 1.81-1.88(m, 4H), 2.03-2.08 (m, 1H), 3.39 (d, J=6.5 Hz, 2H), 3.63 (s, 3H), 4.09(s, 2H), 4.18 (d, =7.3 Hz, 2H), 6.60 (t, =2 Hz, 1H), 6.71 (d, =7.6 Hz,1H), 6.88 (dd, =8.3 Hz, 2.5 Hz, 1H), 7.12 (s, 1H), 7.18-7.23 (m, 3H),7.25-7.35 (m, 3H).

Example 1.44: Preparation of2-(((1r,4r)-4-((3-Benzhydryl-6-oxopyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 7)

To a solution of 6-benzhydrylpyridazin-3(2H)-one (30 mg, 0.114 mmol) andK₂CO₃ (39.5 mg, 0.286 mmol) in DMF (1 mL) at room temperature was addedtert-butyl 2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate(47.2 mg, 0.114 mmol). The reaction was stirred at 40° C. overnight,quenched with water and extracted with EtOAc. The EtOAc extracts weredried over MgSO₄ and concentrated. The residue was treated with 4 M HClin dioxane (0.029 mL, 0.114 mmol) and purified by preparative LCMS togive the title compound as a white solid (20 mg). LCMS m/z=447.2 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.08-0.88 (m, 4H), 1.55-1.64 (m, 1H), 1.65(d, J=12.8 Hz, 2H), 1.80 (d, J=11.6 Hz, 2H), 1.85-1.95 (m, 1H), 3.36 (d,J=6.3 Hz, 2H), 4.0 (d, J=7.08 Hz, 2H), 4.08 (s, 2H), 5.46 (s, 1H), 6.99(d, J=9.3 Hz, 2H), 7.12-7.16 (m, 5H), 7.24-7.34 (m, 5H).

Example 1.45: Preparation of2-(((1r,4r)-4-((6-Oxo-3,4-diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 19)

To a solution of 5,6-diphenylpyridazin-3(2H)-one (30 mg, 0.121 mmol) andpotassium carbonate (50.1 mg, 0.362 mmol) in DMF (1 mL) at roomtemperature was added tert-butyl2-(((1r,4r)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (49.8 mg, 0.121mmol). The reaction was stirred at 40° C. overnight. NaOH (0.201 mL,0.604 mmol) was added and the reaction was again stirred overnightbefore quenched with water and extracted with EtOAc. The EtOAc extractswere concentrated and purified by preparative LCMS to give a white solid(17.1 mg). LCMS m/z=433.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm0.96-1.06 (m, 2H), 1.13-1.23 (m, 2H), 1.61-1.71 (m, 1H), 1.80-1.88 (t,J=16 Hz, 4H), 2.03-2.07 (m, 1H), 3.38 (d, J=6.3 Hz, 2H), 4.09 (s, 2H),4.18 (d, J=7.3 Hz, 2H), 7.10-7.13 (m, 3H), 7.16-7.19 (m, 2H), 7.36-7.24(m, 5H).

Example 1.46: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-6-oxo-3-p-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 47) Step A:Preparation of 3,4-Dibromo-5-p-tolylfuran-2(5H)-one

To a mixture of 3,4-dibromo-5-hydroxyfuran-2(5H)-one (0.5 g, 1.939 mmol)in toluene (5 mL, 1.939 mmol) was added AlCl₃ (0.310 g, 2.327 mmol) atroom temperature. The mixture was stirred at room temperature overnight.The reaction was quenched with water, extracted with EtOAc (3×20 mL),dried over anhydrous MgSO₄, and filtered. The filtrate was concentratedunder reduced pressure to give the title compound without furtherpurification. LCMS m/z=332.8 [M+H]⁺.

Step B: Preparation of 5-Bromo-6-p-tolylpyridazin-3(2H)-one

To a mixture of 3,4-dibromo-5-p-tolylfuran-2(5H)-one (0.5 g, 1.506 mmol)in ethanol (5 mL) was added NH₂NH₂ (0.047 mL, 1.506 mmol) at 0° C. Themixture was stirred at room temperature overnight. The precipitate wasfiltered and dried under reduced pressure to give the title compound asa beige solid (0.22 g). LCMS m/z=264.9 [M+H]⁺.

Step C: Preparation of 5-(3-Chlorophenyl)-6-p-tolylpyridazin-3(2H)-one

In a 10 mL heavy-walled sealed tube, a mixture of5-bromo-6-p-tolylpyridazin-3(2H)-one (0.05 g, 0.189 mmol),3-chlorophenylboronic acid (0.029 g, 0.189 mmol), Pd(Ph₃P)₄ (10.90 mg,9.43 μmol) and K₂CO₃ (0.283 mL, 0.566 mmol) in dioxane (2 mL) was heatedunder microwave irradiation at 130° C. for 2 h. The reaction waspurified by preparative HPLC to give the title compound (0.032 g). LCMSm/z=297.1 [M+H]⁺.

Step D: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-6-oxo-3-p-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

A mixture of 5-(3-chlorophenyl)-6-p-tolylpyridazin-3(2H)-one (30 mg,0.101 mmol), tert-butyl2-(((1s,4s)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate(34.0 mg, 0.101 mmol), potassium tert-butoxide (22.69 mg, 0.202 mmol)and 18-crown-6 (5.34 mg, 0.020 mmol) in DMF (2 mL) was stirred at roomtemperature overnight. The reaction was purified by preparative LCMS togive the title compound as white solid (1 mg). LCMS m/z=481.1 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 1.63-1.44 (m, 8H), 2.04-1.78 (m, 2H), 2.33(s, 3H), 3.52 (d, J=6.8 Hz, 2H), 4.10 (s, 2H), 4.23 (d, J=7.6 Hz, 2H),6.92 (s, 1H), 6.95 (d, J=8 Hz, 1H), 7.03-7.09 (m, 4H), 7.16 (t, J=1.8Hz, 1H), 7.32 (d, 1H, J=8 Hz), 7.20 (t, J=8 Hz, 1H).

Example 1.47: Preparation of2-(((1s,4s)-4-((6-Oxo-3,4-diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 3)

The title compound was prepared using a similar method to the onedescribed in Example 1.43 to give a white solid. LCMS m/z=433.2 [M+H]⁺.

Example 1.48: Preparation of2-(((1s,4s)-4-((3-Benzhydryl-6-oxopyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 4)

The title compound was prepared using a similar method to the onedescribed in Example 1.43 to give a white solid. LCMS m/z=446.9 [M+H]⁺.

Example 1.49: Preparation of2-(((1s,4s)-4-((3-(4-Methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 5)

The title compound was prepared using a similar method to the onedescribed in Example 1.43 to give a white solid. LCMS m/z=463.1 [M+H]⁺.

Example 1.50: Preparation of2-(((1s,4s)-4-((3-(3-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 21) Step A:Preparation of 2-Benzyl-6-hydroxy-5-phenylpyridazin-3(2H)-one

3-Phenylfuran-2,5-dione (2.00 g, 11.5 mmol), benzylhydrazine (3.36 g,17.2 mmol) and acetic acid (2 mL) were heated to 140° C. for 3 h in a 20mL heavy-walled sealed tube under microwave irradiation. Upon cooling, awhite precipitate formed which was filtered and washed three times withhexane and DCM. The white solid was dried under reduced pressure to givethe title compound (11.01 g). LCMS m/z=279.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 5.13 (s, 2H), 7.00 (s, 1H), 7.42-7.26 (m, 5H), 7.49-7.43(m, 3H), 7.66-7.60 (m, 2H).

Step B: Preparation of 2-Benzyl-6-hydroxy-5-phenylpyridazin-3(2H)-one

2-Benzyl-6-hydroxy-5-phenylpyridazin-3(2H)-one (3.33 g, 12.0 mmol) andphosphorus oxychloride (11.2 mL, 119.6 mmol) were heated to 120° C. for0.5 h in a 20 mL heavy-walled sealed tube under microwave irradiation.The mixture was concentrated under reduced pressure and purified bycolumn chromatography to give the title compound as an orange solid(1.466 g). LCMS m/z=297.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 5.32 (s,2H), 6.91 (s, 1H), 7.43-7.31 (m, 5H), 7.55-7.44 (m, 5H).

Step C: Preparation of 6-Chloro-5-phenylpyridazin-3(2H)-one

To a solution of 2-benzyl-6-chloro-5-phenylpyridazin-3(2H)-one (1.45 g,4.89 mmol) in toluene (15 mL) under argon at 90° C. was added aluminumchloride (1.629 g, 12.22 mmol) and the reaction was stirred for 20 min.It was then allowed to cool to room temperature and quenched with water,extracted with EtOAc, dried over MgSO₄ and concentrated. The residue waspurified by preparative HPLC to give the title compound as a white solid(847.6 mg). LCMS m/z=207 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 6.97 (s,1H), 7.41-7.54 (m, 5H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((3-Chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 6-chloro-5-phenylpyridazin-3(2H)-one (407 mg, 1.970mmol) and potassium carbonate (544 mg, 3.94 mmol) in DMF (2 mL) at roomtemperature was added tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (813 mg, 1.970mmol). The reaction was stirred at 40° C. overnight, quenched with waterand extracted with EtOAc. The organic extracts were concentrated andpurified by silica gel column chromatography to give the title compoundas a clear oil (678 mg). LCMS m/z=447.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ ppm 1.49 (s, 9H), 1.58-1.51 (m, 4H), 1.62 (bs, 4H), 1.84-1.90 (m, 1H),2.20-2.27 (m, 1H), 3.45 (d, J=7.07 Hz, 2H), 3.96 (s, 2H), 4.13 (d,J=7.58 Hz, 2H), 6.89 (s, 1H), 7.42-7.44 (m, 2H), 7.45-7.50 (m, 3H).

Step E: Preparation of2-(((1s,4s)-4-((3-(3-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of tert-butyl2-(((1s,4s)-4-((3-chloro-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate(30.0 mg, 0.067 mmol) in dioxane (1 mL) was added the3-fluorophenylboronic acid (10.3 mg, 0.074 mmol), 2 M K₂CO₃ (0.084 mL,0.168 mmol) and Pd(PPh₃)₄(7.76 mg, 0.007 mmol). The reaction was heatedunder microwave irradiation at 130° C. for 2 h. The reaction wasfiltered through a celite column with EtOAc and concentrated. Theresidue was added 4 M HCl in dioxane (0.168 mL, 0.671 mmol) and thereaction was stirred overnight. The reaction was concentrated andpurified by preparative LCMS to give the title compound as a white solid(11.6 mg). LCMS m/z=451.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm1.65-1.42 (m, 8H), 1.83-1.93 (m, 1H), 2.27-2.36 (m, 1H), 3.53 (d, J=6.82Hz, 2H), 4.14-4.09 (m, 2H), 4.29 (d, J=7.83 Hz, 2H), 6.87-6.97 (m, 2H),7.02 (td, J=8.34 Hz, 2.53 Hz, 1H), 7.16-7.09 (m, 3H), 7.21 (td, J=8.02,5.94 Hz, 1H), 7.40-7.29 (m, 3H).

Example 1.51: Preparation of2-(((1s,4s)-4-((3-(2-Fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 40)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=465.1 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.36-1.51 (m, 8H), 1.72-1.84 (m, 1H),2.17-2.24 (m, 1H), 2.28 (s, 3H), 3.39-3.46 (m, 2H), 3.94 (s, 2H),4.12-4.19 (m, 2H), 6.65 (d, J=10 Hz, 1H), 6.91 (s, 1H), 6.92 (d, J=7 Hz,1H), 7.06 (d, J=7.6 Hz, 2H), 7.28-7.14 (m, 4H).

Example 1.52: Preparation of2-(((1s,4s)-4-((3-(4-Chloro-2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 52)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=484.9 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.61-1.47 (m, 8H), 1.81-1.90 (m, 1H), 2.31(s, 1H), 3.52 (d, J=6.5 Hz, 2H), 4.10 (s, 2H), 4.25 (d, J=7.6 Hz, 2H),6.94 (dd, J=8 Hz, 2 Hz, 1H), 7.04 (s, 1H), 7.09 (d, J=7.3 Hz, 2H), 7.16(dd, J=8 Hz, 2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 2H), 7.34(d, J=8 Hz, 1H).

Example 1.53: Preparation of2-(((1s,4s)-4-((3-(4-Chloro-3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 53)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=485.4 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.62-1.48 (m, 8H), 1.82-1.91 (m, 1H),2.28-2.35 (m, 1H), 3.53 (d, J=7 Hz, 2H), 4.11 (s, 2H), 4.25 (d, J=7.5Hz, 2H), 6.83 (dd, J=8 Hz, 2 Hz, 1H), 6.99 (s, 1H), 7.03 (dd, J=8 Hz, 2Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.41-7.30 (m,3H).

Example 1.54: Preparation of2-(((1s,4s)-4-((3-(3-Fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 38)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=487.5 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.57-1.49 (m, 8H), 1.84-1.91 (m, 1H), 2.24(s, 3H), 3.52 (d, =6 Hz, 2H), 2.28-2.34 (m, 1H), 4.23 (d, J=8 Hz, 2H),4.09 (s, 2H), 6.76 (d, J=8 Hz, 1H), 6.87 (d, J=11 Hz, 1H), 6.93 (s, 1H),7.01 (dd, J₁=J₂=8 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.36-7.27 (m, 3H).

Example 1.55: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-p-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 20)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=469.1 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.52-1.44 (m, 8H), 1.83 (bs, 1H), 2.17(bs, 1H), 2.30 (s, 3H), 3.48 (d, J=6 Hz, 2H), 4.02 (s, 2H), 4.20 (d, J=8Hz, 2H), 6.91 (s, 1H), 7.03 (s, 4H), 7.09 (d, J=8 Hz, 2H), 7.31-7.24 (m,3H).

Example 1.56: Preparation of2-(((1s,4s)-4-((3-(4-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 22)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=451.1 [M+H]⁺.

Example 1.57: Preparation of2-(((1s,4s)-4-((3-(2-Chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 23)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=467.4 [M+H]⁺.

Example 1.58: Preparation of2-(((1s,4s)-4-((3-(4-Chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 24)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=467.3 [M+H]⁺.

Example 1.59: Preparation of2-(((1s,4s)-4-((3-(2-Methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 25)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=463.2 [M+H]⁺.

Example 1.60: Preparation of2-(((1s,4s)-4-((3-(3-Methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 26)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=463.2 [M+H]⁺.

Example 1.61: Preparation of2-(((1s,4s)-4-((3-(3-Fluoro-5-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 27)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=481.3 [M+H]⁺.

Example 1.62: Preparation of2-(((1s,4s)-4-((3-(2,3-Fifluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 28)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=469.4 [M+H]⁺.

Example 1.63: Preparation of2-(((1s,4s)-4-((3-(3-Chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 29)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=467.6 [M+H]⁺.

Example 1.64: Preparation of2-(((1s,4s)-4-((3-(2-Fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 35)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=451.1 [M+H]⁺.

Example 1.65: Preparation of2-(((1s,4s)-4-((3-(4-Ethylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 36)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=461.3 [M+H]⁺.

Example 1.66: Preparation of2-(((1s,4s)-4-((6-Oxo-4-phenyl-3-(4-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 37)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=501.2 [M+H]⁺.

Example 1.67: Preparation of2-(((1s,4s)-4-((3-(4-Isopropylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 39)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=475.1 [M+H]⁺.

Example 1.68: Preparation of2-(((1s,4s)-4-((3-(4-(Methylthio)phenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 41)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=479.3 [M+H]⁺.

Example 1.69: Preparation of2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-(1H-pyrazol-4-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 46)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=422.9 [M+H]⁺.

Example 1.70: Preparation of2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 44)

The title compound was prepared using a similar method to the onedescribed in Example 1.50 to give a white solid. LCMS m/z=434.2 [M+H]⁺.

Example 1.71: Preparation of2-(((1s,4s)-4-((4-(3-Fluoro-5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 18) Step A: Preparation of5-Bromo-6-phenylpyridazin-3(2H)-one

To a solution of 3,4-dibromo-5-phenylfuran-2(5H)-one (4.951 g, 15.57mmol) in EtOH (5 mL) at 0° C. was added hydrazine, H₂O (0.840 mL, 17.13mmol). The reaction mixture was stirred at room temperature for 10 minbefore heating to reflux for 2 h. The reaction was cooled to roomtemperature. The precipitate formed was collected by filtration andwashed with cold ethanol to yield the title compound as a pale yellowsolid (2.530 g). LCMS m/z=351 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.47-7.49 (m, 3H), 7.51-7.54 (m, 3H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-((4-Bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate

To a solution of 5-bromo-6-phenylpyridazin-3(2H)-one (1.080 g, 4.30mmol) and potassium carbonate (1.189 g, 8.60 mmol) in DMF (10 mL) atroom temperature was added tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate (1.775 g, 4.30mmol). The reaction was stirred overnight at 40° C., quenched with waterand extracted with EtOAc. The organic extracts were concentrated andpurified by silica gel column chromatography to give the title compoundas a clear oil (431 mg). LCMS m/z=491.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ ppm 1.48 (s, 9H), 1.60-1.49 (m, 4H), 1.80-1.88 (m, 1H), 2.26 (bs, 4H),2.73 (t, J=4.80 Hz, 1H), 3.42 (t, J=3.41 Hz, 2H), 3.94 (s, 2H), 4.15 (d,J=7.58 Hz, 2H), 7.38 (s, 1H), 7.48-7.44 (m, 3H), 7.55-7.50 (m, 2H).

Step C: Preparation of2-(((1s,4s)-4-((4-(3-Fluoro-5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid

To a solution of tert-butyl2-(((1s,4s)-4-((4-bromo-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetate(30 mg, 0.061 mmol) in dioxane (0.5 mL) was added3-fluoro-5-methoxyphenylboronic acid (12.5 mg, 0.073 mmol),Pd(PPh₃)₄(7.05 mg, 0.0061 mmol) and 2 M potassium carbonate (0.076 mL,0.153 mmol). The reaction was heated under microwave irradiation at 130°C. for 1 h. It was filtered through a celite column with EtOAc andconcentrated. The residue was added 4 M HCl in dioxane (10 eq.) andstirred overnight. The mixture was extracted with EtOAc. The EtOAcextracts were concentrated and the residue was purified by preparativeLCMS to give the title compound as a white solid (3.4 mg). LCMSm/z=481.2 [M+H]⁺.

Example 1.72: Preparation of2-(((1s,4s)-4-((4-(3-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 2)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=463.3 [M+H]⁺.

Example 1.73: Preparation of2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-m-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 9)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=447.0 [M+H]⁺.

Example 1.74: Preparation of2-(((1s,4s)-4-((6-Oxo-3-phenyl-4-p-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 10)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=446.9 [M+H]⁺.

Example 1.75: Preparation of2-(((1s,4s)-4-((4-(3-Fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 11)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=451.1 [M+H]⁺.

Example 1.76: Preparation of2-(((1s,4s)-4-((4-(4-Fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 12)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=451.1 [M+H]⁺.

Example 1.77: Preparation of2-(((1s,4s)-4-((4-(2-Chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 13)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=467.3 [M+H]⁺.

Example 1.78: Preparation of2-(((1s,4s)-4-((4-(4-Chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy) acetic Acid (Compound 14)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=467.3 [M+H]⁺.

Example 1.79: Preparation of2-(((1s,4s)-4-((4-(2-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 15)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=463.3 [M+H]⁺.

Example 1.80: Preparation of2-(((1s,4s)-4-((4-(4-Methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 16)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=463.4 [M+H]⁺.

Example 1.81: Preparation of2-(((1s,4s)-4-((4-(2-Fluoro-3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 17)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=481.2 [M+H]⁺.

Example 1.82: Preparation of2-(((1s,4s)-4-((4-(5-Chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 30)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=485.3 [M+H]⁺.

Example 1.83: Preparation of2-(((1s,4s)-4-((4-(3-Chloro-4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 32)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=485.3 [M+H]⁺.

Example 1.84: Preparation of2-(((1s,4s)-4-((4-(3,5-Dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 33)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=501.3 [M+H]⁺.

Example 1.85: Preparation of2-(((1s,4s)-4-((4-(3,4-Dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic Acid (Compound 34)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. LCMS m/z=501.4 [M+H]⁺.

Example 1.86: Preparation of2-(((1s,4s)-4-((4-(3-Chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 6)

The title compound was prepared using a similar method to the onedescribed in Example 1.71 to give a white solid. The title compound wasconverted to its sodium salt by treating it with one equivalent ofsodium methoxide. LCMS m/z=467.5 [M+H]⁺.

Example 1.87: Preparation of2-(((1s,4s)-4-((5-(3-Chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 85) Step A: Preparation of tert-Butyl2-(((1s,4s)-4-((5-(3-chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate

From 5-(3-chlorophenyl)-6-p-tolyl-1,2,4-triazin-3(2H)-one and tert-butyl2-(((1s,4s)-4-(tosyloxymethyl)cyclohexyl)methoxy)acetate, using asimilar method to the one described in Example 1.13, step E, the titlecompound was obtained as an yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm1.43-1.48 (m, 2H), 1.48 (s, 9H), 1.49-1.53 (m, 2H), 1.56-1.65 (m, 4H),1.84-1.92 (m, 1H), 2.29-2.35 (m, 1H), 2.38 (s, 3H), 3.45 (d, J=6.82 Hz,2H), 3.95 (s, 2H), 4.22 (d, J=7.58 Hz, 2H), 7.12-7.17 (m, 4H), 7.19 (t,J=7.83 Hz, 1H), 7.23-7.28 (m, 1H), 7.37-7.43 (m, 1H), 7.61 (t, J=1.77Hz, 1H).

Step B: Preparation of2-(((1s,4s)-4-((5-(3-Chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticAcid (Compound 85)

From tert-butyl2-(((1s,4s)-4-((5-(3-chlorophenyl)-3-oxo-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.13, step F, thetitle compound was obtained as a yellow solid. LCMS m/z=482.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.36-1.54 (m, 6H), 1.68-1.80 (m, 2H),2.12-2.21 (m, 1H), 2.30 (s, 3H), 3.22-3.27 (m, 1H), 3.39 (d, J=7.07 Hz,2H), 3.98 (s, 2H), 4.10 (d, J=7.58 Hz, 2H), 7.13-7.19 (m, 4H), 7.24-7.30(m, 1H), 7.36 (t, J=7.96 Hz, 1H), 7.47 (t, J=1.77 Hz, 1H), 7.51-7.54 (m,1H), 12.49 (s, 1H).

Example 1.88: Preparation of Sodium2-(2-(((1s,4s)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetamido)acetate(Compound 86 Sodium Salt) Step A: Preparation of2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetamido)aceticacid

A mixture of2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid (0.2 g, 0.447 mmol), tert-butyl 2-aminoacetate (0.059 g, 0.447mmol), HATU (0.170 g, 0.447 mmol) and Et₃N (0.187 mL, 1.341 mmol) in DMF(2 ml) was stirred at room temperature overnight. The mixture waspurified by preparative HPLC. To the above product was added HCl (2 mL,8.00 mmol) in 1,4-dioxane. The mixture was stirred at room temperaturefor 4 h. Then the solvent was removed under reduced pressure to give thetitle compound. LCMS m/z=505.3 [M+H]⁺.

Step B: Preparation of sodium2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetamido)acetate

To a mixture of2-(2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetamido)aceticacid (0.1 g, 0.198 mmol) in DCM (5 ml) was added 0.5 M NaOH solution(0.396 ml, 0.198 mmol) at room temperature. The mixture was stirred at25° C. for 2 h. The solvent was removed under reduced pressure to givethe title compound as a yellow solid. ¹H NMR (400 MHz, CDCl3) δ ppm 7.49(d, J=7.6 Hz, 2H), 7.32 (d, J=7.2 Hz, 2H), 7.15 (m, 5H), 4.25 (d, J=7.7Hz, 2H), 4.14 (d, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.49 (d, J=6.4 Hz, 2H),2.37 (s, 3H), 1.84 (m, 1H), 1.61-1.49 (m, 9H).

Example 1.89: Preparation of2-(2-(((1s,4s)-4-((3-Oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)acetamido)ethanesulfonicAcid (Compound 87)

In a 50 mL flask,2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid (1.0 g, 2.235 mmol) was dissolved in thionyl chloride (7.6 g, 63.8mmol) and heated at 80° C. for 6 hours. The mixture was cooled andsolvent was removed. The residue was dissolved in 1,4-dioxane (5 mL) andcooled to 10° C. Taurine (0.839 g, 6.70 mmol) dissolved in aqueoussodium hydroxide solution (0.259 g in 5 mL H₂O) was added. The mixturewas stirred at room temperature. The solvents were removed, and theresidue was dissolved in a mixture of ethyl acetate and 1 N HCl (10 mLeach). The aqueous layer was concentrated and the yellow solid residuewas suspended in ethanol and filtered. The filtrate was concentrated andisopropanol was added. The brown solid was filtered and dried to givethe title compound (100 mg). LCMS m/z=555.8 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.34-1.59 (m, 6H), 1.77 (s, 1H), 2.30 (s, 3H), 2.55 (t,J=6.44 Hz, 1H), 2.71 (s, 1H), 3.05 (s, 3H), 3.16-3.46 (m, 4H), 3.73-3.87(m, 2H), 4.11 (d, 1H), 7.15 (s, 3H), 7.27-7.50 (m, 4H), 7.65 (s, 3H),7.95 (t, J=5.18 Hz, 1H), 9.61 (s, 1H).

Example 2: Homogeneous Time-Resolved Fluorescence (HTRF®) Assay ForDirect cAMP Measurement

Compounds were screened for agonists of the human prostacyclin (PGI2)receptor using the HTRF® assay for direct cAMP measurement (Gabriel etal., ASSAY and Drug Development Technologies, 1:291-303, 2003) andrecombinant CHO-K1 cells stably transfected with human prostacyclinreceptor. CHO-K1 cells were obtained from ATCC® (Manassas, Va.; Catalog# CCL-61). An agonist of the prostacyclin receptor was detected in HTRF®assay for direct cAMP measurement as a compound which increased cAMPconcentration. HTRF® assay also was used to determine EC₅₀ values forprostacyclin receptor agonists.

Principle of the Assay:

The HTRF® assay kit was purchased from Cisbio-US, Inc. (Bedford, Mass.;Catalog #62AM4PEC). The HTRF® assay supported by the kit is acompetitive immunoassay between endogenous cAMP produced by the CHO-K1cells and tracer cAMP labeled with the dye d2. The tracer binding isvisualized by a monoclonal anti-cAMP antibody labeled with Cryptate. Thespecific signal (i.e., fluorescence resonance energy transfer, FRET) isinversely proportional to the concentration of unlabeled cAMP in thestandard or sample.

Standard Curve:

The fluorescence ratio (665 nm/620 nm) of the standards (0.17 to 712 nMcAMP) included in the assay was calculated and used to generate a cAMPstandard curve according to the kit manufacturer's instructions. Thefluorescence ratio of the samples (test compound or compound buffer) wascalculated and used to deduce respective cAMP concentrations byreference to the cAMP standard curve.

Setup of the Assay:

The HTRF® assay was carried out using a two-step protocol essentiallyaccording to the kit manufacturer's instructions, in 20 μL total volumeper well in 384-well plate format (ProxiPlates; PerkinElmer, Fremont,Calif.; catalog #6008280). To each of the experimental wells wastransferred 3000 recombinant CHO-K1 cells in 5 μL assay buffer(phosphate buffered saline containing calcium chloride and magnesiumchloride (Invitrogen, Carlsbad, Calif.; catalog #14040) supplementedwith IBMX (100 gμM) and rolipram (10 gμM) (phosphodiesterase inhibitors;Sigma-Aldrich, St. Louis, Mo.; catalog #15879 and catalog # R6520,respectively) and 0.1% bovine serum albumin (BSA) fraction V(Sigma-Aldrich; catalog # A3059)), followed by test compound in 5 μLassay buffer or 5 μL assay buffer. The plate was then incubated at roomtemperature for 1 h. To each well was then added 5 μL cAMP-d2 conjugatein lysis buffer and 5 μL Cryptate conjugate in lysis buffer according tothe kit manufacturer's instructions. The plate was then furtherincubated at room temperature for 1 h, after which the assay plate wasread.

Assay Readout:

The HTRF® readout was accomplished using a PHERAstar (BMG LABTECH Inc.,Durham, N.C.) or EnVision™ (PerkinElmer, Fremont Calif.) microplatereader.

Certain compounds of the present invention and their correspondingactivity values are shown in TABLE B.

TABLE B human PGI2 receptor Compound No. EC₅₀ (nM) (HTRF ®) 69 8 nM 3131 nM 43 36 nM 67 73 nM

Certain other compounds of the invention had activity values rangingfrom about 2.1 nM to about 4 μM in this assay.

Example 3: Human Platelet Aggregation Inhibition Test

Blood collected from healthy human volunteers in aqueous trisodiumcitrate solution was centrifuged at 150 g for 15 min and the upper layerwas recovered to obtain platelet-rich plasma (PRP). The residual bloodwas centrifuged at 3000 g for 10 min and the supernatant was collectedas platelet-poor plasma (PPP). Platelet concentration in the PRP wasdetermined using the Z series Beckman Coulter particle counter (Beckman,Fullerton, Calif.) and adjusted to 250,000 platelets/μL using PPP. 480μL of PRP was pre-incubated at 37° C. and stirred at 1200 rpm with 10 μLaqueous test compound solution for 1 min prior to induction ofaggregation by the addition of 10 μL of aqueous adenosine diphosphate(ADP) solution to adjust the final ADP concentration in the PRP to1×10⁻⁵ M. The maximal amplitude of aggregation response within 3 min wasdetermined and measured in triplicate using the Chronolog model 490aggregometer (Chrono-log Corp., Havertown, Pa.). Percent inhibition ofaggregation was calculated from the maximum decrease in optical densityof the control (addition of water in place of the test compoundsolution) sample and of the samples containing test compound. The testcompound was added to adjust the final concentration to the range 10⁻⁹to 10⁻⁴ M, and IC₅₀ values were determined by inhibition percentage ofaggregation at each concentration. The results are shown in Table C.

TABLE C Compound No. human PRP IC₅₀ (nM) 69 22 nM 31 21 nM 43 130 nM 867 nM

Certain other compounds of the invention had activity values rangingfrom about 12 nM to about 160 nM in this assay.

It is apparent that the compounds of the present invention markedlyinhibit platelet aggregation in human PRP.

Example 4: Rat Model of Pulmonary Arterial Hypertension

Animals:

Male Wistar rats (100-150 g at start of study) (Charles RiverLaboratories, Wilmington, Mass.) were housed two per cage and maintainedin a humidity-(40-60%) and temperature-(68-72° F.) controlled facilityon a 12 hr: 12 hr light/dark cycle (lights on at 6:30 am) with freeaccess to food (Harlan Teklad, Orange Calif., Rodent Diet 8604) andwater. Rats were allowed one week of habituation to the animal facilitybefore testing.

Rat Monocrotaline Model:

The rat monocrotaline (MCT) model is a standard and well-accepted modelof pulmonary arterial hypertension. MCT induces acute pulmonaryendothelial damage associated with pulmonary vascular inflammation.Subsequently, pulmonary artery smooth muscle cells proliferate,occluding small pulmonary vessels and leading to severe pulmonaryarterial hypertension including right ventricular hypertrophy. (See,e.g., Schermuly et al., Circ. Res., 2004, 94:1101-1108.)

Rats were randomly given a single subcutaneous injection of either 60mg/kg MCT (Sigma, St. Louis, Mo.) or 0.9% saline (sham) and assigned toreceive oral administration of 20% hydroxypropyl beta-cyclodextrin(vehicle) or test compound (30 mg/kg; FIG. 1). 10-11 rats were used pertreatment group. 24 h following MCT administration, test compound orvehicle was administered by oral gavage twice a day for 21 consecutivedays. Heart chamber weights were measured on Day 22. Rats wereanesthetized with intraperitoneal pentobarbital (50 mg/kg), the chestcavity was opened and the heart was excised. The right ventricle wasdissected free from the septum and left ventricle and both parts wereweighed. The ratio of right ventricular (RV) weight to left ventricleplus septum (LV+S) weight (this ratio is indicated as “RV/(LV+S)” inFIG. 1) was calculated as an index of the hypertrophic response to theinduced pulmonary arterial hypertension and, as such, as an index of atest compound's therapeutic efficacy for pulmonary arterialhypertension.

It is apparent from inspection of FIG. 1 that oral administration ofCompound 68 inhibited the hypertrophic response to the induced pulmonaryarterial hypertension and, as such, evidenced therapeutic efficacy forpulmonary arterial hypertension.

Those skilled in the art will recognize that various modifications,additions, substitutions and variations to the illustrative examples setforth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

What is claimed is:
 1. A method for modulating the activity of theprostacyclin receptor in an individual, comprising administering to theindividual a compound having the structure of Formula Ia:

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomerthereof wherein: R¹ is H or C₁-C₈ alkyl; R² is H, C₁-C₈ alkyl, aryl orheteroaryl, wherein the C₁-C₈ alkyl, aryl and heteroaryl are eachoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₈ alkyl, C₁-C₈haloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio and aryl; R³ is H, C₁-C₈ alkyl,aryl or heteroaryl, wherein the C₁-C₈ alkyl, aryl and heteroaryl areeach optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₈ alkyl, C₁-C₈haloalkyl, C₁-C₈ alkoxy, C₁-C₈ alkylthio, and aryl; and X is N or CH. 2.The method of claim 1, wherein the individual is a human that has adisorder selected from the group consisting of platelet aggregation,coronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, ischemia-reperfusion injury, restenosis, atrialfibrillation, blood clot formation, atherosclerosis, atherothrombosis,asthma, a symptom of asthma, diabetic peripheral neuropathy, diabeticnephropathy, diabetic retinopathy, glaucoma or other disease of the eyewith abnormal intraocular pressure, hypertension, inflammation,psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease,transplant rejection, multiple sclerosis, systemic lupus erythematosus,ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, andchronic obstructive pulmonary disorder.
 3. The method of claim 1,wherein the individual is a human that has pulmonary arterialhypertension.
 4. The method of claim 3, wherein the pulmonary arterialhypertension is selected from the group consisting of: (a) idiopathicpulmonary arterial hypertension; (b) familial pulmonary arterialhypertension; (c) pulmonary arterial hypertension associated with acollagen vascular disease selected from the group consisting ofscleroderma, calcinosis, Raynaud's phenomenon, esophageal dysfunction,sclerodactyly and telangiectasias syndrome, systemic lupuserythematosus, rheumatoid arthritis, Takayasu's arteritis, polymyositis,and dermatomyositis; (d) pulmonary arterial hypertension associated witha congenital heart disease selected from the group consisting of atrialseptic defect, ventricular septic defect and patent ductus arteriosus;(e) pulmonary arterial hypertension associated with portal hypertension;(f) pulmonary arterial hypertension associated with humanimmunodeficiency virus infection; (g) pulmonary arterial hypertensionassociated with ingestion of a drug or toxin; (h) pulmonary arterialhypertension associated with hereditary hemorrhagic telangiectasia; (i)pulmonary arterial hypertension associated with splenectomy; (j)pulmonary arterial hypertension associated with significant venous orcapillary involvement; (k) pulmonary arterial hypertension associatedwith pulmonary veno-occlusive disease; and (l) pulmonary arterialhypertension associated with pulmonary capillary hemangiomatosis.
 5. Themethod of claim 1, wherein R¹ is H.
 6. The method of claim 1, wherein Ris C₁-C₆ alkyl.
 7. The method of claim 1, wherein: R² is H, C₁-C₈ alkyl,aryl or heteroaryl, wherein the C₁-C₈ alkyl, aryl and heteroaryl areeach optionally substituted with one or more substituents independentlyselected from the group consisting of fluoro, chloro, methyl, ethyl,isopropyl, trifluoromethyl, methoxy, methylthio, and phenyl; and R³ isH, C₁-C₈ alkyl, aryl or heteroaryl, wherein the C₁-C₈ alkyl, aryl andheteroaryl are each optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, chloro,methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylthio, andphenyl.
 8. The method of claim 1, wherein: R² is C₁-C₈ alkyl, aryl orheteroaryl, each optionally substituted; and R³ is C₁-C₈ alkyl, aryl orheteroaryl, each optionally substituted.
 9. The method of claim 1,wherein: R² is H, methyl, phenyl, 1H-pyrazol-4-yl, pyridinyl,thiophen-2-yl or thiophen-3-yl, wherein the methyl, phenyl, pyridinyl,thiophen-2-yl and thiophen-3-yl are each optionally substituted with oneor more substituents independently selected from the group consisting offluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, methoxy,methylthio and phenyl; and R³ is H, methyl, phenyl, 1H-pyrazol-4-yl,pyridinyl, thiophen-2-yl or thiophen-3-yl, wherein the methyl, phenyl,pyridinyl, thiophen-2-yl and thiophen-3-yl are each optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, chloro, methyl, ethyl, isopropyl,trifluoromethyl, methoxy, methylthio, and phenyl.
 10. The method ofclaim 1, wherein R² is H, benzhydryl, phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,4-isopropylphenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-(methylthio)phenyl,2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methylphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl,5-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,3-fluoro-4-methylphenyl, 3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl,2-fluoropyridin-4-yl, 2-chloropyridin-4-yl, 5-chloropyridin-3-yl,6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,2-methylpyridin-4-yl, thiophen-2-yl, thiophen-3-yl,4-methylthiophen-2-yl, or 5-methylthiophen-2-yl; and R³ is H,benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl,4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-4-methylphenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl,2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 6-chloropyridin-3-yl,5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-4-yl,thiophen-2-yl, thiophen-3-yl, 4-methylthiophen-2-yl, or5-methylthiophen-2-yl.
 11. The method of claim 1, wherein: R² isbenzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methylphenyl,4-ethylphenyl, 4-isopropylphenyl, 4-(trifluoromethyl)phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-(methylthio)phenyl,2,3-difluorophenyl, 2-fluoro-4-methylphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methoxyphenyl, pyridin-3-yl, pyridin-4-yl,6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,thiophen-2-yl or thiophen-3-yl; and R³ is H, phenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl,2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 5-methylpyridin-3-yl,2-methylpyridin-4-yl, thiophen-2-yl, 4-methylthiophen-2-yl, or5-methylthiophen-2-yl.
 12. The method of claim 1, wherein X is N. 13.The method of claim 1, wherein X is CH.
 14. The method of claim 1,wherein the stereoisomer of the compound of Formula Ia has the structureof Formula Ic:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R² is benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl,2-fluoro-4-methylphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methoxyphenyl, pyridin-3-yl, pyridin-4-yl,6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,thiophen-2-yl or thiophen-3-yl; and R³ is H, phenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl,2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 5-methylpyridin-3-yl,2-methylpyridin-4-yl, thiophen-2-yl, 4-methylthiophen-2-yl, or5-methylthiophen-2-yl.
 15. The method of claim 1, wherein thestereoisomer of the compound of Formula Ia has the structure of FormulaIe:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R² is benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl,2-fluoro-4-methylphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methoxyphenyl, pyridin-3-yl, pyridin-4-yl,6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,thiophen-2-yl or thiophen-3-yl; and R³ is H, phenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl,2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 5-methylpyridin-3-yl,2-methylpyridin-4-yl, thiophen-2-yl, 4-methylthiophen-2-yl, or5-methylthiophen-2-yl.
 16. The method of claim 1, wherein thestereoisomer of the compound of Formula Ia has the structure of FormulaIg:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R² is benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl,2-fluoro-4-methylphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methoxyphenyl, pyridin-3-yl, pyridin-4-yl,6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,thiophen-2-yl or thiophen-3-yl; and R³ is H, phenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl,2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 5-methylpyridin-3-yl,2-methylpyridin-4-yl, thiophen-2-yl, 4-methylthiophen-2-yl, or5-methylthiophen-2-yl.
 17. The method of claim 1, wherein thestereoisomer of the compound of Formula Ia has the structure of FormulaIi:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R² is benzhydryl, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-(methylthio)phenyl, 2,3-difluorophenyl,2-fluoro-4-methylphenyl, 4-chloro-2-fluorophenyl,4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methoxyphenyl, pyridin-3-yl, pyridin-4-yl,6-chloropyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl,thiophen-2-yl or thiophen-3-yl; and R³ is H, phenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 1H-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl,2-fluoropyridin-3-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl,2-chloropyridin-4-yl, 5-chloropyridin-3-yl, 5-methylpyridin-3-yl,2-methylpyridin-4-yl, thiophen-2-yl, 4-methylthiophen-2-yl, or5-methylthiophen-2-yl.
 18. The method of claim 1, wherein thestereoisomer of the compound of Formula Ia is selected from the groupconsisting of:2-(((1s,4s)-4-((3-oxo-5,6-di-p-tolyl-1,2,4-triazin-2(3H)-ylmethyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-ylmethyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5,6-bis(4-fluorophenyl)-3-oxo-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-(4-fluorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5-(3-chlorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-(4-methoxyphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5-(3-methoxyphenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-(4-chlorophenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1r,4r)-4-((6-(2-fluoro-4-methylphenyl)-3-oxo-5-phenyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1r,4r)-4-((3-oxo-5-phenyl-6-p-tolyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-oxo-6-(pyridin-3-yl)-5-p-tolyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-oxo-5-(pyridin-4-yl)-6-p-tolyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1r,4r)-4-((3-oxo-6-phenyl-5-m-tolyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1r,4r)-4-((5-(3-fluorophenyl)-3-oxo-6-phenyl-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1r,4r)-4-((3-oxo-5-m-tolyl-6-p-tolyl-1,2,4-triazin-2(3H)-yl)methyl)cyclohexyl)methoxy)aceticacid; or2-(((1s,4s)-4-((3-oxo-6-phenyl-5-(thiophen-2-yl)-1,2,4-triazin-2(3H-yl)methyl)cyclohexyl)methoxy)aceticacid; and a pharmaceutically acceptable salt, solvate or hydrate of anyone of the preceding compounds.
 19. The method of claim 1, wherein thestereoisomer of the compound of Formula Ia is selected from the groupconsisting of:2-(((1r,4r)-4-((4-(3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-oxo-3,4-diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1s,4s)-4-((3-benzhydryl-6-oxopyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((3-(4-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1r,4r)-4-((3-benzhydryl-6-oxopyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((4-(2,3-difluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-oxo-3-phenyl-4-m-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-oxo-3-phenyl-4-p-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(2-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(4-chlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(2-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(4-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(2-fluoro-3-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-fluoro-5-methoxyphenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1r,4r)-4-((6-oxo-3,4-diphenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1s,4s)-4-((6-oxo-4-phenyl-3-p-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((3-(3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(2-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(2-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(3-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(3-fluoro-5-methoxyphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(2,3-difluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(3-chlorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(5-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-chloro-2-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(3-chloro-4-fluorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1s,4s)-4-((4-(3,5-dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((4-(3,4-dichlorophenyl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-ethylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(4-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(3-fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-isopropylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(2-fluoro-4-methylphenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-(methylthio)phenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((6-oxo-3-phenyl-4-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((4-(5-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((6-oxo-3-phenyl-4-(1H-pyrazol-4-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((4-(3-chlorophenyl)-6-oxo-3-p-tolylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(4-methylthiophen-2-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((4-(2-methylpyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((3-(4-chloro-2-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(4-chloro-3-fluorophenyl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(2-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((4-(6-fluoropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1s,4s)-4-((4-(2-chloropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(pyridin-4-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1s,4s)-4-((4-(2-fluoropyridin-4-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((4-(5-methylpyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((6-oxo-4-phenyl-3-(thiophen-3-yl)pyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid;2-(((1s,4s)-4-((3-(5-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; 2-(((1s,4s)-4-((3-(6-methylpyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)acetic acid;2-(((1s,4s)-4-((3-(6-chloropyridin-3-yl)-6-oxo-4-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; or2-(((1s,4s)-4-((4-(5-chloropyridin-3-yl)-6-oxo-3-phenylpyridazin-1(6H)-yl)methyl)cyclohexyl)methoxy)aceticacid; and a pharmaceutically acceptable salt, solvate or hydrate of anyone of the preceding compounds.